Nicotine salts, co-crystals, and salt co-crystal complexes

ABSTRACT

The invention provides certain nicotine salts, co-crystals, and salt co-crystals and provides novel polymorphic forms of certain nicotine salts. In particular, nicotine salts with mucic acid, 3,5-dihydroxybenzoic acid, and 2,3-dihydroxybenzoic acid, and crystalline polymorphic forms of nicotine 4-acetamidobenzoate, nicotine gentisate, and nicotine 1-hydroxy-2-naphthoate are described. The invention further provides methods of preparation and characterization of such nicotine salts, co-crystals, and salt co-crystals and polymorphic forms thereof. In addition, tobacco products, including smoking articles, smokeless tobacco products, and electronic smoking articles comprising nicotine salts, co-crystals, and/or salt co-crystals are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional ApplicationNo. 62/003,295, filed May 27, 2014, which is incorporated by referenceherein.

FIELD OF THE INVENTION

The present invention relates to various salts, co-crystals, and saltco-crystals of nicotine and to compositions and products (e.g., tobaccoproducts) into which such salts, co-crystals, and salt co-crystals canbe incorporated.

BACKGROUND OF THE INVENTION

Cigarettes, cigars and pipes are popular smoking articles that employtobacco in various forms. Such smoking articles are used by heating orburning tobacco, and aerosol (e.g., smoke) is inhaled by the smoker.Electronic smoking articles are a further type of tobacco product, whichcomprise a reservoir and heating system for the delivery ofaerosolizable materials. Tobacco also may be enjoyed in a so-called“smokeless” form. Particularly popular smokeless tobacco products areemployed by inserting some form of processed tobacco ortobacco-containing formulation into the mouth of the user.

Various types of cigarette components, including tobacco types, tobaccoblends, top dressing and casing materials, blend packing densities andtypes of paper wrapping materials for tobacco rods, are set forth in theart. See, for example, the various representative types of cigarettecomponents, as well as the various cigarette designs, formats,configurations and characteristics, that are set forth in Johnson,Development of Cigarette Components to Meet Industry Needs, 52^(nd)T.S.R.C. (September 1998); U.S. Pat. No. 5,101,839 to Jakob et al.; UU.S. Pat. No. 5,159,944 to Arzonico et al.; U U.S. Pat. No. 5,220,930 toGentry and U.S. Pat. No. 6,779,530 to Kraker; US Pat. App. Pub. Nos.2005/0016556 to Ashcraft et al.; 2005/0066986 to Nestor et al.;2005/0076929 to Fitzgerald et al.; 2006/0272655 to Thomas et al.;2007/0056600 to Coleman, III et al.; and 2007/0246055 to Oglesby, eachof which is incorporated herein by reference.

Exemplary smokeless tobacco formulations, ingredients, and processingmethodologies are set forth in U.S. Pat. No. 1,376,586 to Schwartz; U.S.Pat. No. 3,696,917 to Levi; U.S. Pat. No. 4,513,756 to Pittman et al.;U.S. Pat. No. 4,528,993 to Sensabaugh, Jr. et al.; 4,624,269 to Story etal.; U.S. Pat. No. 4,991,599 to Tibbetts; U.S. Pat. No. 4,987,907 toTownsend; U.S. Pat. No. 5,092,352 to Sprinkle, III et al.; U.S. Pat. No.5,387,416 to White et al.; U.S. Pat. No. 6,668,839 to Williams; U.S.Pat. No. 6,834,654 to Williams; U.S. Pat. No. 6,953,040 to Atchley etal.; U.S. Pat. No. 7,032,601 to Atchley et al.; and U.S. Pat. No.7,694,686 to Atchley et al.; US Pat. Pub. Nos. 2004/0020503 to Williams;2005/0115580 to Quinter et al.; 2006/0191548 to Strickland et al.;2007/0062549 to Holton, Jr. et al.; 2007/0186941 to Holton, Jr. et al.;2007/0186942 to Strickland et al.; 2008/0029110 to Dube et al.;2008/0029116 to Robinson et al.; 2008/0173317 to Robinson et al.;2008/0196730 to Engstrom et al.; 2008/0209586 to Neilsen et al.;2008/0305216 to Crawford et al.; 2009/0065013 to Essen et al.;2009/0293889 to Kumar et al.; 2010/0291245 to Gao et al. and2011/0139164 to Mua et al.; PCT WO 04/095959 to Arnarp et al. and WO2010/132444 A2 to Atchley; each of which is incorporated herein byreference. Exemplary smokeless tobacco products that have been marketedinclude those referred to as CAMEL Snus, CAMEL Orbs, CAMEL

Strips and CAMEL Sticks by R. J. Reynolds Tobacco Company; GRIZZLY moisttobacco, KODIAK moist tobacco, LEVI GARRETT loose tobacco and TAYLOR'SPRIDE loose tobacco by American Snuff Company, LLC; KAYAK moist snuffand CHATTANOOGA CHEW chewing tobacco by Swisher International, Inc.;REDMAN chewing tobacco by Pinkerton Tobacco Co. LP; COPENHAGEN moisttobacco, COPENHAGEN Pouches, SKOAL Bandits, SKOAL Pouches, RED SEAL longcut and REVEL Mint Tobacco Packs by U.S. Smokeless Tobacco Company; andMARLBORO Snus and Taboka by Philip Morris USA.

Many smoking devices have been proposed through the years asimprovements upon, or alternatives to, smoking products that requirecombusting tobacco for use. Many of those devices purportedly have beendesigned to provide the sensations associated with cigarette, cigar, orpipe smoking, but without delivering considerable quantities ofincomplete combustion and pyrolysis products that result from theburning of tobacco. To this end, there have been proposed numeroussmoking products, flavor generators, and medicinal inhalers that utilizeelectrical energy to vaporize or heat a volatile material, or attempt toprovide the sensations of cigarette, cigar, or pipe smoking withoutburning tobacco to a significant degree. See, for example, the variousalternative smoking articles, aerosol delivery devices and heatgenerating sources set forth in the background art described in U.S.Pat. No. 7,726,320 to Robinson et al., U U.S. Pat. Pub. No. 2013/0255702to Griffith Jr. et al., U.S. Pat. Pub. Nos. 2014/0000638 to Sebastian etal., 2014/0060554 to Collett et al., 2014/0060555 to Chang et al.,2014/0096781 to Sears et al., 2014/0096782 to Ampolini et al., and2015/0059780 to Davis et al., which are incorporated herein by referencein their entireties.

Certain of these types of smoking articles, smokeless tobacco products,and electronic smoking articles comprise a tobacco extract, which insome products may be purified such that the extract is comprisedprimarily of nicotine. However, tobacco extracts comprising a highpercentage of nicotine (including extracts comprising at least about90%, at least about 95%, and at least about 99% nicotine by weight) aretypically in oil form. As such, nicotine extracts can be difficult tohandle and incorporate into certain tobacco products.

It would be desirable to provide such nicotine-based extracts in a formthat is amenable to incorporation in tobacco products. It would furtherbe desirable to incorporate such extracts into an enjoyable form of atobacco product and to provide processes for preparing such forms ofnicotine-based extracts as well as for preparing various types ofcompositions and products incorporating such forms of nicotine-basedextracts.

SUMMARY OF THE INVENTION

The present invention provides various forms of nicotine that can beapplicable to a wide range of products, including tobacco products.Particularly, the present application describes nicotine salts,co-crystals, and salt co-crystals and the preparation of such nicotinesalts, co-crystals, and salt co-crystals. It also describes theincorporation of such nicotine salts, co-crystals, and/or saltco-crystals into various products including tobacco products (e.g.,smoking articles, smokeless tobacco products, and electronic smokingarticles) and pharmaceutical products.

In a first aspect of the invention is provided a nicotine salt orcrystalline polymorphic form selected from the group consisting of: asalt of nicotine and mucic acid; a salt of nicotine and3,5-dihydroxybenzoic acid; a salt of nicotine and 2,3-dihydroxybenzoicacid; a crystalline polymorphic form of nicotine 1-hydroxy-2-naphthoate,wherein the form is characterized by an X-ray powder diffraction patternhaving peaks at one or more (including all) of the following 2-thetadiffraction angles: 15.6, 16.1, 20.5, 22.5, and 27.1; a crystallinepolymorphic form of nicotine 4-acetamidobenzoate, wherein the form ischaracterized by an X-ray powder diffraction pattern having peaks at oneor more (including all) of the following 2-theta diffraction angles:16.839, 17.854, 20.134, and 23.265; and a crystalline polymorphic formof nicotine gentisate, wherein the form is characterized by an X-raypowder diffraction pattern having peaks at one or more (including all)of the following 2-theta diffraction angles: 13.000, 19.017, 20.194, and21.000. A given percentage of the material, e.g., at least about 50% ofthe material, can be in crystalline form.

In one embodiment, a salt formed from nicotine and mucic acid,characterized by an X-ray powder diffraction pattern having peaks at oneor more of the following 2-theta diffraction angles: 14.289, 15,449,19.66, and 20.412 is provided. In an additional embodiment, a saltformed from nicotine and 2,3-dihydroxybenzoic acid is provided, whereinthe form is characterized by an X-ray powder diffraction pattern havingpeaks at one or more of the following 2-theta diffraction angles: 12.4,12.5, 15.2, 18.3, 19.7, 20.3, 20.9, 24.9, 25.2, 26.5, and 30.4.

In another embodiment, a salt formed from nicotine and3,5-dihydroxybenzoic acid is provided, wherein the form is an anhydrousform characterized by an X-ray powder diffraction pattern having peaksat one or more of the following 2-theta diffraction angles: 12.7, 17.8,19.7, 20.2, 21.3, 24.5, 24.9, 25.8, and 29.8. In a further embodiment, asalt formed from nicotine and 3,5-dihydroxybenzoic acid is provided,wherein the form is a hydrated form characterized by an X-ray powderdiffraction pattern having peaks at one or more of the following 2-thetadiffraction angles: 10.7, 13.4, 15.0, 17.2, 17.3, 19.0, 21.4, 21.6,22.2, 22.6, 22.9, 24.3, 25.1, 25.5, and 29.7. A given sample of saltformed from nicotine and 3,5-dihydroxybenzoic acid can comprisecompletely and/or substantially one single form, or can comprise amixture of two or more forms (including, but not limited to, theanhydrous and dihydrate forms referenced above) in varying amounts.

The nicotine salts, co-crystals, and salt co-crystals described in thepresent application are generally applicable for use in a range ofproducts including, but not limited to, smoking articles, electronicsmoking articles, smokeless tobacco products (e.g., lozenges and gums),pharmaceutical products, and the like. Accordingly, in another aspect ofthe invention is provided a product incorporating one or more nicotinesalts, co-crystals, and/or salt co-crystals as described herein. Invarious embodiments, electronic smoking articles, smokeless tobaccoproducts, and/or pharmaceutical products incorporating one or more ofthe salts, co-crystals, and/or salt co-crystal complexes disclosedherein are provided.

For example, in one aspect, the disclosure provides an electronicsmoking article comprising an inhalable substance medium containedwithin a cartridge body and a heating member positioned to provide heatto at least a portion of the inhalable substance medium, wherein theinhalable substance medium comprises a nicotine salt or crystallinepolymorphic form as disclosed herein (e.g., one or more salts orcrystalline polymorphic forms selected from the group consisting of: asalt of nicotine and mucic acid; a salt of nicotine and3,5-dihydroxybenzoic acid; a salt of nicotine and 2,3-dihydroxybenzoicacid; a crystalline polymorphic form of nicotine 1-hydroxy-2-naphthoate,wherein the form is characterized by an X-ray powder diffraction patternhaving peaks at one or more (including all) of the following 2-thetadiffraction angles: 15.6, 16.1, 20.5, 22.5, and 27.1; a crystallinepolymorphic form of nicotine 4-acetamidobenzoate, wherein the form ischaracterized by an X-ray powder diffraction pattern having peaks at oneor more (including all) of the following 2-theta diffraction angles:16.839, 17.854, 20.134, and 23.265; and a crystalline polymorphic formof nicotine gentisate, wherein the form is characterized by an X-raypowder diffraction pattern having peaks at one or more (including all)of the following 2-theta diffraction angles: 13.000, 19.017, 20.194, and21.000).

The inhalable substance medium can further comprise, for example, one ormore of glycerin, water, and a flavorant. The amount of nicotine salt orpolymorph form incorporated can vary and, in some embodiments, can bethat amount sufficient to provide nicotine in an amount of about 0.01 mgto about 0.5 mg, about 0.05 mg to about 0.3 mg, or about 0.1 mg to about0.2 mg per puff on the article.

In another aspect, the disclosure provides a smokeless tobacco productcomprising a nicotine salt or crystalline polymorphic form as describedherein (e.g., one or more salts or crystalline polymorphic formsselected from the group consisting of: a salt of nicotine and mucicacid; a salt of nicotine and 3,5-dihydroxybenzoic acid; a salt ofnicotine and 2,3-dihydroxybenzoic acid a crystalline polymorphic form ofnicotine 1-hydroxy-2-naphthoate, wherein the form is characterized by anX-ray powder diffraction pattern having peaks at one or more (includingall) of the following 2-theta diffraction angles: 15.6, 16.1, 20.5,22.5, and 27.1; a crystalline polymorphic form of nicotine4-acetamidobenzoate, wherein the form is characterized by an X-raypowder diffraction pattern having peaks at one or more (including all)of the following 2-theta diffraction angles: 16.839, 17.854, 20.134, and23.265; and a crystalline polymorphic form of nicotine gentisate,wherein the form is characterized by an X-ray powder diffraction patternhaving peaks at one or more (including all) of the following 2-thetadiffraction angles: 13.000, 19.017, 20.194, and 21.000). Exemplarysmokeless tobacco products include, but are not limited to, loose moistsnuff (e.g., snus); loose dry snuff; chewing tobacco; pelletized tobaccopieces; extruded or formed tobacco strips, pieces, rods, cylinders orsticks; finely divided ground powders; finely divided or milledagglomerates of powdered pieces and components; flake-like pieces;molded tobacco pieces; gums; rolls of tape-like films; readilywater-dissolvable or water-dispersible films or strips; meltablecompositions; lozenges; pastilles; and capsule-like materials possessingan outer shell and an inner region.

In a further aspect, the disclosure provides a pharmaceutical productcomprising a nicotine salt or crystalline polymorphic form as describedherein (e.g., one or more salts or crystalline polymorphic formsselected from the group consisting of: a salt of nicotine and mucicacid; a salt of nicotine and 3,5-dihydroxybenzoic acid; a salt ofnicotine and 2,3-dihydroxybenzoic acid; a salt of nicotine and1-hydroxy-2-naphthoic acid; a crystalline polymorphic form of nicotine4-acetamidobenzoate, wherein the form is characterized by an X-raypowder diffraction pattern having peaks at one or more of the following2-theta diffraction angles: 16.839, 17.854, 20.134, and 23.265; and acrystalline polymorphic form of nicotine gentisate, wherein the form ischaracterized by an X-ray powder diffraction pattern having peaks at oneor more of the following 2-theta diffraction angles: 13.000, 19.017,20.194, and 21.000). Such products can be, for example, in a formselected from the group consisting of a pill, tablet, lozenge, capsule,caplet, pouch, gum, inhaler, solution, and cream. One exemplary lozengeformulation comprises one or more of the nicotine salts or crystallinepolymorphic forms disclosed herein and at least about 50% by weightisomalt.

Additionally, in a still further aspect, the disclosure provides methodsof preparing certain nicotine salts and crystalline polymorphic forms.For example, the disclosure provides methods of preparing nicotinemucate, comprising combining mucic acid and nicotine to form a solid andisolating the solid. The disclosure provides methods of preparingnicotine 3,5-dihydroxybenzoate, comprising combining3,5-dihydroxybenzoic acid and nicotine to form a solid and isolating thesolid. In some embodiments, the resulting salt can comprise an anhydrousform. A hydrated form (e.g., a dihydrate form) can, in certainembodiments, be prepared by exposing the anhydrous form to humidity asdisclosed herein. The disclosure provides methods of preparing nicotine2,3-dihydroxybenzoate, comprising combining 2,3-dihydroxybenzoic acidand nicotine to form a solid and isolating the solid.

The disclosure also provides methods of preparing a crystallinepolymorphic form of nicotine 1-hydroxy-2-naphthoate, comprisingcombining 1-hydroxy-2-naphthoic acid and nicotine to form a solid andisolating the solid. The disclosure further provides a method ofpreparing a crystalline polymorphic form of nicotine4-acetamidobenzoate, comprising combining 4-acetamidobenzoic acid andnicotine in equimolar amounts in a solvent (e.g., tetrahydrofuran) toform a solid and isolating the solid. The disclosure also provides amethod of preparing a crystalline polymorphic form of nicotinegentisate, comprising combining gentisic acid and nicotine in equimolaramounts in a solvent (e.g., tetrahydrofuran) to form a solid andisolating the solid.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to provide an understanding of embodiments of the invention,reference is made to the appended drawings, which are not necessarilydrawn to scale, and in which reference numerals refer to components ofexemplary embodiments of the invention. The drawings are exemplary only,and should not be construed as limiting the invention.

FIG. 1 is an x-ray powder diffraction pattern of nicotine mucate;

FIG. 2 is a ¹H NMR spectrum of nicotine mucate;

FIG. 3 is an x-ray powder diffraction pattern of crystalline nicotine4-acetamidobenzoate, showing the experimental pattern and the patterncalculated from the single crystal x-ray structure;

FIGS. 4A and 4B are views of crystal structures obtained for twoindependent molecules of nicotine 4-acetamidobenzoate and FIG. 4C is aview of the crystal packing of nicotine 4-acetamidobenzoate;

FIG. 5 is an x-ray powder diffraction pattern of crystalline nicotinegentisate, showing the experimental pattern and the pattern calculatedfrom the single crystal x-ray structure;

FIG. 6A is a view of a crystal structure obtained for nicotine gentisateand FIG. 6B is a view of the crystal packing of nicotine gentisate;

FIG. 7 is an x-ray powder diffraction pattern of nicotine3-hydroxybenzoate;

FIG. 8 is an x-ray powder diffraction pattern of nicotine malate;

FIG. 9 is an x-ray powder diffraction pattern of anhydrous nicotine3,5-dihydroxybenzoate, showing the experimental pattern and the patterncalculated from the single crystal x-ray structure;

FIG. 10 is a ¹H NMR spectrum of anhydrous nicotine3,5-dihydroxybenzoate;

FIG. 11 is an x-ray powder diffraction pattern of nicotine3,5-dihydroxybenzoate dihydrate;

FIG. 12 is a ¹H NMR spectrum of nicotine 3,5-dihydroxybenzoatedihydrate;

FIG. 13 is a view of a crystal structure obtained for anhydrous nicotine3,5-dihydroxybenzoate;

FIG. 14A is a plot showing hydrogen bonding in the asymmetric unit ofanhydrous nicotine 3,5-dihyroxybenzoate and FIG. 14B is a view of thecrystal packing of anhydrous nicotine 3,5-dihydroxybenzoate;

FIG. 15 is an x-ray powder diffraction pattern of nicotine2,3-dihydroxybenzoate;

FIG. 16 is a ¹H NMR spectrum of nicotine 2,3-dihydroxybenzoate;

FIG. 17 is an x-ray powder diffraction pattern of nicotine1-hydroxy-2-naphthoate;

FIG. 18 is a ¹H NMR spectrum of nicotine 1-hydroxy-2-naphthoate;

FIG. 19 is an exploded perspective view of a smoking article having theform of a cigarette, showing the smokable material, the wrappingmaterial components, and the filter element of the cigarette;

FIG. 20 is a cross-sectional view of a smokeless tobacco productembodiment, taken across the width of the product, showing an outerpouch filled with a smokeless tobacco composition of the invention; and

FIG. 21 is a cross-sectional view of an electronic smoking article,which can encompass a variety of combinations of components useful informing an electronic aerosol delivery device.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention now will be described more fully hereinafter. Thisinvention may, however, be embodied in many different forms and shouldnot be construed as limited to the embodiments set forth herein; rather,these embodiments are provided so that this disclosure will be thoroughand complete, and will fully convey the scope of the invention to thoseskilled in the art. As used in this specification and the claims, thesingular forms “a,” “an,” and “the” include plural referents unless thecontext clearly dictates otherwise. Reference to “dry weight percent” or“dry weight basis” refers to weight on the basis of dry ingredients(i.e., all ingredients except water).

The present invention relates to nicotine salts, co-crystals, and saltco-crystals and methods of preparation thereof. It also relates toproducts (including tobacco products and pharmaceutical products) thatcomprise one or more nicotine salts, co-crystals, and/or saltco-crystals. In certain embodiments, nicotine provided in one or moresuch forms can advantageously be isolated in a physical form that is animprovement over neat nicotine, which is a hygroscopic, oily liquid. Forexample, in certain embodiments, nicotine salts, co-crystals, and/orsalt co-crystals as described herein can be in an easier to handle formthan neat nicotine (e.g., a solid or semi-solid form), can be providedin a higher purity form than neat nicotine, and/or can exhibit greaterthermodynamic, physical, and/or chemical stability (e.g., a higherresistance to oxidation, reduced risk of hydrate formation, and/or alonger shelf life) than neat nicotine. In some embodiments, nicotinesalts, co-crystals, and/or salt co-crystals can provide increasedstability in the presence of relevant excipients in the product intowhich the salt, co-crystal, and/or salt co-crystal will be incorporated,as compared to neat nicotine. In some embodiments, nicotine salts,co-crystals, and salt co-crystals can exhibit a significant degree ofwater-solubility, rendering them applicable for incorporation within awide range of compositions and products.

Nicotine itself can be isolated and/or treated such that it is in one oftwo enantiomeric forms or it may be provided in racemic form. Nicotineis naturally occurring in levorotatory, (L)-nicotine form (also known as(−)-nicotine or S-nicotine). In the salts, co-crystals, and saltco-crystals provided herein, the nicotine is generally in the form of(L)-nicotine, although this disclosure is not intended to preclude thepreparation and application of dextrorotatory ((D)-nicotine) salts,co-crystals, and salt co-crystals or racemic forms of nicotine in thedisclosed salts, co-crystals, and salt co-crystals. Accordingly,nicotine salts, co-crystals, and salt co-crystals can be in anenantiomerically highly pure form (i.e., (L)- or (D)-form) or in racemicform as described herein.

A “nicotine salt” is a form of nicotine characterized by the interactionbetween nicotine in ionic form and a coformer in ionic form (e.g., anacid) via the transfer of one or more protons from the coformer donor tothe nicotine acceptor. The structure of nicotine is such that itcomprises two nitrogen atoms that are capable of accepting protons froma coformer and, accordingly, it can be present in non-protonated,mono-protonated, and/or di-protonated form in a given sample.

Certain nicotine salts are presently known. For example, nicotinesulfate has been sold as a pesticide and nicotine bitartrate dihydrate(also known as nicotine hydrogen tartrate) is a commercially available,water-soluble nicotine salt. Various other salts have been studied,including a nicotine acetic acid salt (which forms a viscous oil) aswell as, for example, nicotine citrates and nicotine malates. See, forexample, the types of ingredients and techniques set forth in U.S. Pat.No. 2,033,909 to Cox et al. and Perfetti, Beitrage Tabakforschung Int.,12, 43-54 (1983). Additionally, certain salts of nicotine have beenavailable from sources such as Pfaltz and Bauer, Inc. and K&KLaboratories, Division of ICN Biochemicals, Inc. Exemplary knownnicotine salts include nicotine salts such as nicotine tartrate andnicotine bitartrate, nicotine chloride (e.g., nicotine hydrochloride andnicotine dihydrochloride), nicotine sulfate, nicotine perchlorate,nicotine ascorbate, nicotine fumarate, nicotine citrate, nicotinemalate, nicotine lactate, nicotine aspartate, nicotine salicylate,nicotine tosylate, nicotine succinate, nicotine pyruvate, and nicotinesalt hydrates (e.g., nicotine zinc chloride monohydrate). A nicotinesalt with levulinic acid is discussed in US Pat. App. Pub. No.2011/0268809 and Int. App. Pub. No. PCT/US2011/033928, both to Brinkleyet al., which are incorporated herein by reference. See also, forexample, U.S. Pat. No. 4,830,028 to Lawson et al. and U.S. Pat. No.5,031,646 to Lippiello et al. and Leonard, Ind. Eng. Chem. 48: 1331-1341(1956). However, certain previously disclosed nicotine salts of organicacids are not commonly crystalline and can exhibit a range ofstoichiometries, which may make them unsuitable for use in certainapplications.

A “nicotine co-crystal” is a form of nicotine comprising nicotine and atleast one other component (“coformer”), both in neutral form.Co-crystals are typically characterized by a crystalline structure,which is generally held together by freely reversible, non-covalentinteractions. Co-crystals are typically made up of nicotine and at leastone other component in a defined stoichiometric ratio. In someembodiments, co-crystals can encompass hydrates, solvates, andclathrates. Co-crystals can comprise nicotine in combination with anorganic and/or an inorganic component. Co-crystals can generally bedistinguished from salts by the absence of a proton transfer between thecomponents (i.e., the nicotine and the one or more coformers) in aco-crystal. According to the U.S. Food and Drug Administration'sGuidance for Industry (April 2013), a co-crystal is defined as a solidthat is a crystalline material composed of two or more molecules in thesame crystal lattice, where the components are in a neutral state andinteract via nonionic interactions. See U.S. Department of Health andHuman Services, Food and Drug Administration, Guidance for Industry:Regulatory Classification of Pharmaceutical Co-Crystals (April 2013),which is incorporated herein by reference.

A “nicotine salt co-crystal” is a type of hybrid structure with bothsalt and co-crystal characteristics. Typically, a nicotine moleculewithin a salt co-crystal is associated with at least two coformers(which may be the same or different), wherein one coformer is in ionicform (e.g., an acid) and transfers a proton to the nicotine molecule andwherein a second coformer does not transfer a proton to the nicotinemolecule.

The stoichiometry of the salts, co-crystals, and salt co-crystalsdescribed herein can vary. For example, in certain embodiments, wheretwo components (i.e., nicotine and one coformer) are present, thenicotine: coformer stoichiometry can range in certain embodiments fromabout 5:1 to about 1:5 nicotine: coformer. Where more than one coformeris used to form a nicotine salt, co-crystal, or salt co-crystal, theratios of the coformers with respect to both the nicotine and to oneanother can also vary. In preferable embodiments, a given sample of thesalts, co-crystals, and salt co-crystals provided according to thepresent disclosure exhibit substantially one single stoichiometry.

The salts, co-crystals, and salt co-crystals described herein can, insome embodiments, exist in various polymorphic and pseudopolymorphicforms. Polymorphism is the ability of a crystalline material to exist inmore than one form or crystal structure. Polymorphism can result, e.g.,from the existence of different crystal packing structures (packingpolymorphism) or from the existence of different conformers of the samemolecule (conformational polymorphism). Pseudopolymorphism is the resultof hydration or solvation of a material and is also referred to assolvomorphism.

The salts, co-crystals, and salt co-crystals of the present disclosurecan incorporate nicotine derived from some form of a plant of theNicotiana species (e.g., some form of tobacco). The nicotine can be, forexample, in the form of a highly purified tobacco extract. Variousmethods are known for the isolation and purification of nicotine fromtobacco (including, but not limited to, extraction from tobacco withwater; extraction from tobacco with organic solvents; steam distillationfrom tobacco; or pyrolytic degradation of tobacco and distillation ofnicotine therefrom). For exemplary extraction methods, see for example,U.S. Pat. Nos. 2,822,306 and 4,153,063 to Roselius et al. and US Pat.App. Pub. No. 2008/0302377 to Kauryzbaev et al., which are incorporatedherein by reference.

The selection of the plant from the Nicotiana species (from which suchextracts and other tobacco materials that can be combined with thesalts, co-crystals, and/or salt co-crystals described herein areobtained) can vary; and in particular, the types of tobacco or tobaccosmay vary. Tobaccos that can be employed include flue-cured or Virginia(e.g., K326), burley, sun-cured (e.g., Indian Kurnool and Orientaltobaccos, including Katerini, Prelip, Komotini, Xanthi and Yamboltobaccos), Maryland, dark, dark-fired, dark air cured (e.g., Passanda,Cubano, Jatin and Bezuki tobaccos), light air cured (e.g., NorthWisconsin and Galpao tobaccos), Indian air cured, Red Russian andRustica tobaccos, as well as various other rare or specialty tobaccos.Descriptions of various types of tobaccos, growing practices andharvesting practices are set forth in Tobacco Production, Chemistry andTechnology, Davis et al. (Eds.) (1999), which is incorporated herein byreference. Nicotiana species can be derived using genetic-modificationor crossbreeding techniques (e.g., tobacco plants can be geneticallyengineered or crossbred to increase or decrease production of or toother change certain components, characteristics or attributes).Additional information on types of Nicotiana species suitable for use inthe present invention can be found in US Pat. App. Pub. No. 2012/0192880to Dube et al., which is incorporated by reference herein. Tobaccoplants can be grown in greenhouses, growth chambers, or outdoors infields, or grown hydroponically.

The portion or portions of the plant of the Nicotiana species usedaccording to the present invention can vary. For example, virtually allof the plant (e.g., the whole plant) can be harvested, and employed assuch. Alternatively, various parts or pieces of the plant can beharvested or separated for further use after harvest. For example, theleaves, stem, stalk, roots, lamina, flowers, seed, and various portionsand combinations thereof, can be isolated for further use or treatment.The plant material of the invention may thus comprise an entire plant orany portion of a plant of the Nicotiana species. See, for example, theportions of tobacco plants set forth in US Pat. App. Pub. Nos.2011/0174323 to Coleman, III et al. and 2012/0192880 to Dube et al.,which are incorporated by reference herein.

The plant of the Nicotiana species can be employed in either an immatureor mature form, and can be used in either a green form or a cured form,as described in 2012/0192880 to Dube et al., which is incorporated byreference herein. The tobacco material can be subjected to varioustreatment processes such as, refrigeration, freezing, drying (e.g.,freeze-drying or spray-drying), irradiation, yellowing, heating, cooking(e.g., roasting, frying or boiling), fermentation, bleaching orotherwise subjected to storage or treatment for later use. Exemplaryprocessing techniques are described, for example, in US Pat. App. Pub.Nos. 2009/0025739 to Brinkley et al. and 2011/0174323 to Coleman, III etal., which are incorporated by reference herein. At least a portion ofthe plant of the Nicotiana species can be treated with enzymes and/orprobiotics before or after harvest, as discussed in US Pat. App. Pub.Nos. 2013/0269719 to Marshall et al. and 2014/0020694 to Moldoveanu,which are incorporated herein by reference.

A harvested portion or portions of the plant of the Nicotiana speciescan be physically processed. A portion or portions of the plant can beseparated into individual parts or pieces (e.g., roots can be removedfrom stalks, stems can be removed from stalks, leaves can be removedfrom stalks and/or stems, petals can be removed from the remainingportion of the flower). The harvested portion or portions of the plantcan be further subdivided into parts or pieces (e.g., shredded, cut,comminuted, pulverized, milled or ground into pieces or parts that canbe characterized as filler-type pieces, granules, particulates or finepowders). The harvested portion or portions of the plant can besubjected to external forces or pressure (e.g., by being pressed orsubjected to roll treatment). When carrying out such processingconditions, the harvested portion or portions of the plant can have amoisture content that approximates its natural moisture content (e.g.,its moisture content immediately upon harvest), a moisture contentachieved by adding moisture to the harvested portion or portions of theplant, or a moisture content that results from the drying of theharvested portion or portions of the plant. As such, harvested portionor portions of the plant can be used as such as components of tobaccoproducts, or processed further.

To provide a nicotine extract, the plant of the Nicotiana species orportions thereof is typically subjected to one or more types ofprocessing conditions. Typical separation processes can include one ormore process steps (e.g., solvent extraction using polar solvents,organic solvents, and/or supercritical fluids), chromatography,distillation, filtration, recrystallization, and/or solvent-solventpartitioning. Exemplary extraction and separation solvents or carriersinclude water, alcohols (e.g., methanol or ethanol), hydrocarbons (e.g.,heptane and hexane), halogenated hydrocarbons (e.g.,monofluorotrichloromethane (Freon 11), dichlorotrifluoroethane (Freon123), and the like), diethyl ether, methylene chloride, andsupercritical carbon dioxide. See, for example, the description ofisolated tobacco components and techniques for isolation in U.S. Pat.No. 4,967,771 to Fagg et al., US Pat. App. Pub. Nos. 2011/0174323 toColeman, III et al.; 2011/0259353 to Coleman, III et al.; 2012/0192880to Dube et al.; 2012/0192882 to Dube et al.; and 2012/0211016 to Byrd,Jr. et al., which are incorporated by reference herein.

Although the nicotine incorporated within the salts, co-crystals, andsalt co-crystals of the present disclosure are commonly derived fromsome form of a plant of the Nicotiana species as outlined above, thesource of the nicotine is not limited thereto. For example, in someembodiments, nicotine may be provided synthetically. In someembodiments, nicotine may be obtained from another source (e.g., anothertype of plant).

Nicotine is typically isolated (e.g., as described above) in neat(liquid) form. According to the present invention, nicotine is modifiedsuch that it is provided in other forms by incorporating the nicotine asa component of a salt, co-crystal, or salt co-crystal, e.g., in the formof an oil, solid, semi-solid, etc. In some embodiments, certain salts,co-crystals, and salt co-crystals are desirably provided in solid form,e.g., solid, crystalline form. Advantageously (although notnecessarily), coformers (including acids) that are combined withnicotine to form such nicotine salts, co-crystals, or salt co-crystalsare “GRAS” (Generally Regarded As Safe) according to the U.S. Food andDrug Administration. Furthermore, it is beneficial (although again, notnecessary) for the nicotine salts, co-crystals, and/or salt co-crystalsproduced thereby to also be GRAS.

In one embodiment, nicotine mucate (also called nicotine galactarate) isprovided. Nicotine mucate is formed from nicotine and mucic acid (alsoknown as (2S,3R,4S,5R)-2,3,4,5-tetrahydroxyhexanedioic acid, hexaricacid, galactaric acid, meso-galactaric acid, saccharolactic acid,tetrahydroxyadipic acid, tetrahydroxyhexanedioic acid). In one aspect, anicotine mucate salt is provided having a stoichiometry of from about2:1 nicotine: acid to about 1:2 nicotine to acid. In certainembodiments, a nicotine mucate salt is provided having a stoichiometryof between about 2:1 nicotine: acid and about 1:1 nicotine: acid (i.e.,having no more than 1 equivalent of acid per nicotine).

It is noted that, in some embodiments, the exact form of nicotine mucateprepared according to the present disclosure may not be known. Asdescribed in Example 1, in one embodiment, nicotine mucate was preparedand analyzed by ¹H NMR, which indicated that the solid consisted of 0.72equivalents of acid. Although not intending to be limited, thisdetermination may be consistent with a nicotine mucate salt co-crystal,e.g., having a hemi mucate salt structure with additional mucic acidmolecules associated therewith (by hydrogen bonding). However, it ispossible that the nicotine mucate prepared and reported herein is, infact, a hemi mucate salt (i.e., consisting of 0.5 equivalents of acid).In certain embodiments, nicotine mucate is provided in solid form andmay be in crystalline and/or amorphous form. An exemplary x-ray powderdiffraction (XRPD) pattern of a sample comprising crystalline andamorphous forms of nicotine mucate is provided in FIG. 1. The nicotinemucate can be described as exhibiting an XRPD pattern having peaks atone or more of the following 2-theta diffraction angles: 14.289°,15,449°, 19.66°, and 20.412°. Full characterization data, including atable of all relevant peaks in the x-ray diffraction pattern, isprovided in Example 1. A ¹H NMR spectrum of this material is provided inFIG. 2.

Advantageously, in certain embodiments, a sample of nicotine mucate isprovided wherein at least a particular percentage comprises the formdescribed herein. For example, in some embodiments, nicotine mucatecomprising at least about 70%, at least about 75%, at least about 80%,at least about 85%, at least about 90%, at least about 95%, at leastabout 97%, at least about 98%, or at least about 99% of the formdescribed herein by weight is provided

Consistent with a crystalline form, nicotine mucate may, in someembodiments, exhibit a relatively sharp melting point. For example, incertain embodiments, nicotine mucate can exhibit a discrete meltingpoint with an onset between about 120° C. and about 125° C. (e.g., about123° C.). Consistent with an amorphous form, nicotine mucate may, incertain embodiments, lack a discrete melting point. Amorphous nicotinemucate may exhibit a broad melting range. In certain embodiments,nicotine mucate can exhibit a melting range with an onset of about 133°C. Samples that exist as a mixture of amorphous and crystalline nicotinemucate may exhibit both a relatively sharp melting point and a broadmelting range. The ratio of crystalline to amorphous nicotine mucate canvary and may be, for example, between about 10:90 and about 90:10.

In certain embodiments, polarized light microscopy (PLM) of nicotinemucate displays irregular birefringent particles, typically less thanabout 10 μm. However, it is noted that the particles may exhibitdifferent sizes and/or shapes, which may be dependent upon the method ofpreparation and/or the ratio of amorphous to crystalline solid presentin the analyzed sample.

In another aspect of the present disclosure, a specific crystalline formof nicotine 4-acetamidobenzoate has been isolated and identified. Saltsof acetamidobenzoic acid have been previously described. See, e.g.,Lasslo et al., J. Amer. Pharm. Assoc. (1912-1977) (1959), 48, 345-7 andGialdi et al., Farmaco, Edizione Scientifica (1959), 14, 15-24, whichare incorporated herein by reference. According to certain aspects ofthe present invention, a novel crystalline form is provided anddescribed according to certain parameters described herein.

This novel crystalline form of nicotine 4-acetamidobenzoate can, in someembodiments, be characterized by the x-ray powder diffraction (XRPD)pattern, as shown in FIG. 3. Agreement is good between the experimentalpattern from the bulk sample and the pattern calculated from the singlecrystal x-ray structure. The XRPD patterns are obtained as described inthe Experimental section of the present disclosure.

Full characterization data for nicotine 4-acetamidobenzoate, including atable of all relevant peaks in the x-ray diffraction pattern of nicotine4-acetamidobenzoate, is provided in Example 2. The nicotine4-acetamidobenzoate can be described as exhibiting an XRPD patternhaving peaks at one or more of the following 2-theta diffraction angles:16.839°, 17.854°, 20.134°, and 23.265°. Consistent with a crystallineform, this nicotine 4-acetamidobenzoate form exhibits a discrete meltingpoint with an onset between about 130° C. and about 135° C. (e.g., about134° C.).

Advantageously, in certain embodiments, a sample of nicotine4-acetamidobenzoate is provided wherein at least a particular percentagecomprises the crystalline polymorphic form described herein. Forexample, in some embodiments, nicotine 4-acetamidobenzoate comprising atleast about 70%, at least about 75%, at least about 80%, at least about85%, at least about 90%, at least about 95%, at least about 97%, atleast about 98%, or at least about 99% of the polymorphic form describedherein by weight is provided.

A single crystal x-ray diffraction (SCXRD) structure has been obtainedfor this crystalline form of nicotine 4-acetamidobenzoate, as shown inFIGS. 4A and 4B (showing two independent molecules of nicotine4-acetamidobenzoate). The SCXRD structure was obtained as described inthe Experimental section of the present disclosure. Anisotropic atomicdisplacement ellipsoids for the non-hydrogen atoms are shown at the 50%probability level. Hydrogen bonds are shown as dashed lines. Hydrogenatoms are displayed with an arbitrarily small radius. In certainembodiments, at least a given percentage of the crystalline nicotine4-acetamidobenzoate provided as described herein is a single crystallineform. For example, in some embodiments, at least about 50%, at leastabout 60%, at least about 70%, at least about 80%, or at least about 90%of the crystalline 4-acetamidobenzoate is in a single crystalline form.

It is apparent from the x-ray structure that a proton has beentransferred, confirming that the form is a salt. The x-ray structurefurther indicates that the nicotine is the S enantiomer. The SCXRDstructure of the nicotine 4-acetamidobenzoate further indicates ahydrogen bonded head to tail arrangement of the acid molecules (with theacid carbonyl of one molecule hydrogen bonding to an NH functionality ina second), with nicotine molecules attached at regular intervals. Thisform of nicotine 4-acetamidobenzoate can be described has having amonoclinic crystal system.

In certain embodiments, the disclosed nicotine 4-acetamidobenzoateexhibits physical properties that render it suitable for incorporationinto various products. For example, in some embodiments, the disclosedform is not significantly hygroscopic, with the bulk of its observedwater uptake coming in the 80-90% relative humidity range. Accordingly,storage of this form is possible, given appropriate controls on therelative humidity level of the environment in which it is stored.

In another aspect of the present disclosure, a specific crystalline formof nicotine 2,5-dihydroxybenzoate (i.e., nicotine gentisate) has beenisolated and identified. Salts of nicotine gentisate have beenpreviously described. See, e.g., Perfetti, Beitraege zur TabakforschungInternational (1983), 12(2), 43-54; Dezelic et al., Spectrochimica Acta,Part A: Molecular and Biomolecular Spectroscopy (1967), 23(4), 1149-53;Nikolin et al., Arhiv za Higijenu Rada i Toksikologiju (1966), 17(3),303-8; Dezelic et al., Glasnik Hemicara Technol. Bosne Hercegovine etal. (1965), 13-14, 27-36; and Dezelic et al., Glasnik Drustva Hem.Technol. NR Bosne Hercegovine (1961), 10, 55-62, which are incorporatedherein by reference. According to certain aspects of the presentinvention, a novel crystalline form of nicotine gentisate is providedand described according to certain parameters described herein.

This novel crystalline form of nicotine gentisate can, in someembodiments, be characterized by the x-ray powder diffraction (XRPD)pattern, as shown in FIG. 5. Agreement is good between the experimentalpattern from the bulk sample and the pattern calculated from the singlecrystal x-ray structure. The XRPD patterns are obtained as described inthe Experimental section of the present disclosure. Fullcharacterization data, including a table of all relevant peaks in thex-ray diffraction pattern, is provided in Example 3. The nicotinegentisate can be described as exhibiting an XRPD pattern having peaks atone or more of the following 2-theta diffraction angles: 13.000°,19.017°, 20.194°, and 21.000°. Consistent with a crystalline form, thisnicotine 2,5-hydroxybenzoate form exhibits a discrete melting point withan onset between about 145° C. and about 150° C. (e.g., about 149° C.).

Advantageously, in certain embodiments, a sample of nicotine gentisateis provided wherein at least a particular percentage comprises thecrystalline polymorphic form described herein. For example, in someembodiments, nicotine gentisate comprising at least about 70%, at leastabout 75%, at least about 80%, at least about 85%, at least about 90%,at least about 95%, at least about 97%, at least about 98%, or at leastabout 99% of the polymorphic form described herein by weight isprovided.

A single crystal x-ray diffraction (SCXRD) structure has been obtainedfor this crystalline form of nicotine gentisate, as shown in FIG. 6A.The SCXRD structure was obtained as described in the Experimentalsection of the present disclosure. Anisotropic atomic displacementellipsoids for the non-hydrogen atoms are shown at the 50% probabilitylevel. Hydrogen bonds are shown as dashed lines. Hydrogen atoms aredisplayed with an arbitrarily small radius. In certain embodiments, atleast a given percentage of the crystalline nicotine gentisate providedas described herein is a single crystalline form. For example, in someembodiments, at least about 50%, at least about 60%, at least about 70%,at least about 80%, or at least about 90% of the crystalline gentisateis in a single crystalline form. The crystal packing of the nicotinegentisate obtained is provided in FIG. 6B.

It is apparent from the x-ray structure of nicotine gentisate that aproton has been transferred, confirming that the form is a salt. TheSCXRD structure of the nicotine gentisate further indicates a hydrogenbonded head to tail arrangement of the acid molecules (with one moleculehydrogen bonding to a second molecule), with nicotine molecules attachedat regular intervals. This form of nicotine gentisate can be describedas having a monoclinic crystal system.

In certain embodiments, the disclosed nicotine gentisate exhibitsphysical properties that render it suitable for incorporation intovarious products. In fact, the disclosed form of nicotine gentisateexhibits lower hygroscopicity and better thermal stability than thecommercially available ditartrate dihydrate, e.g., as evidenced by thethermogravimetric analysis (TGA) and differential scanning calorimetry(DSC) studies described herein.

In further aspects, nicotine 3-hydroxybenzoate and nicotine malate areprovided. XRPD patterns for these salts are provided at FIGS. 7 and 8,respectively. Additional data for these salts is provided in Examples 4and 5.

In another aspect of the invention, nicotine 3,5-dihydroxybenzoate isprovided. Nicotine 3,5-dihydroxybenzoate is formed from nicotine and3,5-dihydroxybenzoic acid. In one aspect, a nicotine3,5-dihydroxybenzoate salt is provided having a stoichiometry of about1:1 nicotine: acid. In certain embodiments, nicotine3,5-dihydroxybenzoate is provided in solid form and may be incrystalline and/or amorphous form.

In some embodiments, nicotine 3,5-dihydroxybenzoate can exist inanhydrous and/or one or more hydrated (e.g., dihydrate) forms.Accordingly, nicotine 3,5-dihydroxybenzoate salts can undergo formchanges when exposed to varying humidity levels. An exemplary powderdiffraction (XRPD) pattern of a sample of anhydrous nicotine3,5-dihydroxybenzoate is provided in FIG. 9. Agreement is good betweenthe experimental pattern from the bulk sample and the pattern calculatedfrom the single crystal x-ray structure. The anhydrous nicotine3,5-dihydroxybenzoate can be described as exhibiting an XRPD patternhaving peaks at one or more of the following 2-theta diffraction angles:12.7°, 17.8°, 19.7°, 20.2°, 21.3°, 24.5°, 24.9°, 25.8°, and 29.8°. Fullcharacterization data, including a table of all relevant peaks in thex-ray diffraction pattern, is provided in Example 6. A ¹H NMR spectrumof the anhydrous form of this material is provided in FIG. 10.

An XRPD pattern of nicotine 3,5-dihydroxybenzoate dihydrate (prepared byexposure of the anhydrous form to humidity) is provided in FIG. 11. Thenicotine 3,5-dihydroxybenzoate dihydrate can be described as exhibitingan XRPD pattern having peaks at one or more of the following 2-thetadiffraction angles: 10.7°, 13.4°, 15.0°, 17.2°, 17.3°, 19.0°, 21.4°,21.6°, 22.2°, 22.6°, 22.9°, 24.3°, 25.1°, 25.5°, and 29.7°. Fullcharacterization data, including a table of all relevant peaks in thex-ray diffraction pattern, is provided in Example 6. A ¹H NMR spectrumof the dihydrate form of this material is provided in FIG. 12. It isnoted that VH-XRPD experiments confirmed the existence of this dihydrateform (exhibiting the same XRPD diffractogram as the material resultingfrom storage of the anhydrous form at 25° C./96% relative humidity). Thedihydrate form in some embodiments can be converted back to theanhydrous form referenced above upon heating.

A single crystal x-ray diffraction (SCXRD) structure has been obtainedfor the crystalline form of anhydrous nicotine 3,5-hydroxybenzoate, asshown in FIG. 13. The SCXRD structure was obtained as described in theExperimental section of the present disclosure. Anisotropic atomicdisplacement ellipsoids for the non-hydrogen atoms are shown at the 50%probability level. Hydrogen bonds are shown as dashed lines. Hydrogenatoms are displayed with an arbitrarily small radius. In certainembodiments, at least a given percentage of the crystalline nicotine3,5-dihydroxybenzoate provided as described herein is a singlecrystalline form. For example, in some embodiments, at least about 50%,at least about 60%, at least about 70%, at least about 80%, or at leastabout 90% by weight of the crystalline 3,5-dihydroxybenzoate is in asingle crystalline form. A plot showing hydrogen bonding in theasymmetric unit of anhydrous nicotine 3,5-dihyroxybenzoate is presentedin FIG. 14A and the crystal packing of the anhydrous nicotine3,5-dihydroxybenzoate obtained is provided in FIG. 14B.

Consistent with a crystalline form, nicotine 3,5-dihydroxybenzoate may,in some embodiments, exhibit a relatively sharp melting point. Forexample, in certain embodiments, nicotine 3,5-dihydroxybenzoate canexhibit a discrete melting point with an onset of about 138° C. for theanhydrous form. The dihydrate form appears to melt at about 137° C.(with endotherms from 50-100° C.) and, although not intending to belimited by theory, it is believed that the dihydrate is being convertedto the anhydrous form over the temperature range of 50-100° C. and itthe converted anhydrous form then melts at about 137° C. In certainembodiments, polarized light microscopy of nicotine3,5-dihydroxybenzoate reveals irregular particles, typically less thanabout 10 μm. However, it is noted that the particles may exhibitdifferent sizes and/or shapes, which may be dependent upon the method ofpreparation and/or the ratio of amorphous to crystalline solid presentin the analyzed sample.

In another aspect, nicotine 2,3-dihydroxybenzoate is provided. Nicotine2,3-dihydroxybenzoate is formed from nicotine and 2,3-dihydroxybenzoicacid. In one aspect, a nicotine 2,3-dihydroxybenzoate salt is providedhaving a stoichiometry of about 1:1 nicotine: acid. In certainembodiments, nicotine 2,3-dihydroxybenzoate is provided in solid formand may be in crystalline and/or amorphous form.

In certain embodiments, nicotine 2,3-dihydroxybenzoate is provided insolid form and may be in crystalline and/or amorphous form. An exemplaryx-ray powder diffraction (XRPD) pattern of a sample comprising nicotine2,3-dihydroxybenzoate is provided in FIG. 15. The nicotine2,3-dihydroxybenzoate can be described as exhibiting an XRPD patternhaving peaks at one or more of the following 2-theta diffraction angles:12.4°, 12.5°, 15.2°, 18.3°, 19.7°, 20.3°, 20.9°, 24.9°, 25.2°, 26.5°,and 30.4°. Full characterization data, including a table of all relevantpeaks in the x-ray diffraction pattern, is provided in Example 7. A ¹HNMR spectrum of this material is provided in FIG. 16.

Consistent with a crystalline form, nicotine 2,3-dihydroxybenzoate may,in some embodiments, exhibit a relatively sharp melting point. Forexample, in certain embodiments, nicotine 2,3-dihydroxybenzoate canexhibit a discrete melting point with an onset of about 157° C. for theanhydrous form. In certain embodiments, polarized light microscopy ofnicotine 3,5-dihydroxybenzoate reveals irregular particles, typicallyless than about 10 μm. However, it is noted that the particles mayexhibit different sizes and/or shapes, which may be dependent upon themethod of preparation and/or the ratio of amorphous to crystalline solidpresent in the analyzed sample. Generally, the nicotine2,3-dihydroxybenzoate exhibited low hygroscopicity and no change of formwhen exposed to humidity, properties desirable for easy handling.

In another aspect, a specific crystalline form of nicotine1-hydroxy-2-naphthoate (i.e., nicotine xinafoate) has been isolated andidentified. A salt of nicotine 1-hydroxy-2-naphthoate has beenpreviously described. See Dezelic et al., Glasnik Drustva HemicaraTechnol. Bosne Hercegoveni et al. (1961), 10:55-62, which isincorporated herein by reference. According to certain aspects of thepresent invention, a novel crystalline form of nicotine1-hydroxy-2-naphthoate is provided and described according to certainparameters described herein.

The novel crystalline form of nicotine 1-hydroxy-2-naphthoate can, insome embodiments, be characterized by the x-ray powder diffraction(XRPD) pattern, as shown in FIG. 17. The nicotine 1-hydroxy-2-naphthoatecan be described as exhibiting an XRPD pattern having peaks at one ormore of the following 2-theta diffraction angles: 11.2°, 14.4°, 15.6°,16.1°,17.0°, 19.2°, 20.5°, 22.2°, 22.5°, 25.4°, 25.7°, and 27.1°. Fullcharacterization data, including a table of all relevant peaks in thex-ray diffraction pattern, is provided in Example 8. The nicotine1-hydroxy-2-naphthoate form can be described as exhibiting an XRPDpattern having peaks at one or more of the following 20theta diffractionangles: 15.6°, 16.1°, 20.5°, 22.5°, and 27.1°. Consistent with acrystalline form, this nicotine 1-hydroxy-2-naphthoate form exhibits adiscrete melting point, with an onset between about 110° C. and about115° C. (e.g., about 111° C.).

Advantageously, in certain embodiments, a sample of nicotine1-hydroxy-2-naphthoate is provided wherein at least a particularpercentage comprises the crystalline polymorphic form described herein.For example, in some embodiments, nicotine 1-hydroxy-2-naphthoatecomprising at least about 70%, at least about 75%, at least about 80%,at least about 85%, at least about 90%, at least about 95%, at leastabout 97%, at least about 98%, or at least about 99% of the polymorphicform described herein by weight is provided

A ¹H NMR spectrum of the disclosed nicotine 1-hydroxy-2-naphthoate isprovided in FIG. 18. This nicotine 1-hydroxy-2-napthoate form hascertain desirable physical characteristics. For example, the nicotine1-hydroxy-2-napthoate form disclosed herein exhibited low hygroscopicityand no change of form when exposed to humidity, properties desirable foreasy handling.

One skilled in the art will understand that all diffraction pattern dataprovided herein should not be construed as absolute and, accordingly,the nicotine salts, co-crystals, and salt co-crystals of the inventionare not limited to particles having XRPD patterns identical to FIGS. 1,3, 5, 7, 8, 9, 11, 15, and 17. Any nicotine salts, co-crystals, or saltco-crystals having XRPD patterns substantially the same as those ofFIGS. 1, 3, 5, 7, 8, 9, 11, 15, and 17 will be considered to fall withinthe scope of the invention. A person skilled in the art of X-ray powderdiffraction is able to judge the substantial identity of X-ray powderdiffraction patterns. Generally, a measurement error of a diffractionangle in an X-ray powder diffractogram is about 2-theta=0.5° or less(more suitably, about 2-theta=0.2° or less) and such degree of ameasurement error should be taken into account when considering theX-ray powder diffraction pattern in FIGS. 1, 3, 5, 7, 8, 9, 11, 15, and17 or the peak values provided herein. In other words, the peaks inFIGS. 1, 3, 5, 7, 8, 9, 11, 15, and 17 and the peak values giventhroughout the specification can be viewed, in certain embodiments, asbeing +/−0.5° or +/−0.2°. See Fundamentals of Powder Diffraction andStructural Characterization, Pecharsky and Zavalij, Kluwer AcademicPublishers, 2003.

Other nicotine salts, co-crystals, and salt co-crystals are alsoencompassed by the present disclosure. For a list of pharmaceuticallyacceptable counter-ions, see Handbook of PharmaceuticalSalts—Properties, Selection, and Use, P. Heinrich Stahl, Camille G.Wermuth (Eds.) VHCA (Verlag Helvetica Chemica Acta-Zurich), Wiley-VCH(New York) 2002, which is incorporated herein by reference. For example,certain coformers useful for reaction with the nicotine, which mayresult in the formation of a salt, co-crystal, or salt co-crystalinclude, but are not limited to: acetic acid; adipic acid; ascorbicacid; capric (decanoic) acid; citric acid; D-glucuronic acid; D-gluconicacid; DL-lactic acid; L-lactic acid; galactaric (mucic) acid; hippuric(N-benzoylglycine) acid; hydrochloric acid; L-aspartic acid; L-glutamicacid; L-glutaric acid; glycerophosphoric acid; glycolic acid; lauricacid; DL-malic acid; L-malic acid; DL-tartaric acid; L-tartaric acid;palmitic acid; phosphoric acid; sebacic (1,8-octanedicarboxylic) acid;stearic (octadecanoic) acid; succinic acid; sulfuric acid; andthiocyanic acid (HS-CN). Other exemplary coformers for reaction with thenicotine, which may result in the formation of a salt, co-crystal, orsalt co-crystal include, but are not limited to, (+)-camphoric acid;1,5-naphthalenedisulfonic acid; 1-hydroxy-2-naphthoic (xinafoic) acid;2,5-dihydroxybenzoic (gentisic) acid; benzenesulfonic acid; benzoicacid; caprylic (octanoic) acid; cyclamic acid; ethanesulfonic acid;fumaric acid; D-glucoheptonic acid; 4-hydroxybenzoic acid; isobutyricacid; ketoglutaric (2-oxo-glutaric) acid; 2-ketobutyric acid;lactobionic acid; maleic acid; malonic acid; methanesulfonic acid;naphthalene-2-sulfonic acid; nicotinic acid; oleic (Z-octadecenoic)acid; orotic acid; oxalic acid; pamoic acid; pivalic acid; propionicacid; L-pyroglutamic acid; and p-toluenesulfonic acid.

Certain other types of coformers are generally associated withpharmacological effects and are not typically preferred for thepreparation of salts, co-crystals, and salt co-crystals. Althoughcomplexes of nicotine with such coformers may not be preferred, incertain specialized embodiments, they may be reacted with nicotine toform salts, co-crystals, and/or salt co-crystals. Such coformersinclude, but are not limited to, (1S)-camphor-10-sulfonic acid;4-acetamidobenzoic acid; 4-aminosalicylic acid,N-acetyl-4-aminosalicylic acid; caproic (hexanoic) acid; dichloroaceticacid; hydrobromic acid; DL-mandelic acid; L-mandelic acid; nitric acid;formic acid; salicylic acid; cinnamic (e.g., trans-cinnamic) acid; andundecylenic acid. Other exemplary coformers that may form salts,co-crystals, and/or salt co-crystals with nicotine include, but are notlimited to, isothionic acid; lauric (dodecanoic) acid; 2-hydroxybenzoicacid; trans-2-hexanoic acid; trimesic acid; and 5-nitroisophthalic acid.

Various other coformers can be used to provide nicotine in the form of asalt, co-crystal, or co-crystal salt. Exemplary co-formers include, butare not limited to, L-proline, tromethamine; urea, xylitol; caffeine;glycine/glycine anhydride; vanillin; methyl 4-hydroxybenzoate(methylparaben); succinamide; L-alanine; mannitol; L-phenylalanine;saccharin; propylparaben; N-methylglucamine; L-tyrosine; gentisic acid;sorbic acid; benzoic acid; L-methionine; maltol; L-lysine, tromethamine;nicotinamide; isonicotinamide; phenylalanine; benzoquinone;terephthalaldehyde; 2,4-dihydroxybenzoic acid; and 4-hydroxybenzoicacid.

Additional coformers include pyruvic acid, 1-hydroxy-2-naphthoic acid,4-aminobenzoic acid, 3,5-dihydroxybenzoic acid, 2,3-dihydroxybenzoicacid, 3,4-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, vanillicacid, ethyl vanillin, isonicotinic acid, gallic acid, menthol (e.g.,racemic menthol or (−)-menthol), paracetamol, aspirin, ibuprofen,naproxen, ketoprofen, flurbiprofen, glucose, serine, malic acid,acetamide, sulfacetamide, benzoic acid, 4-aminobenzoic acid, creatine,2-hydroxyethanesulfonic acid, clofibric acid, taurine (tauric acid),iproniazid, L-histadine, L-arginine, L-asparagine, glutamine,L-cysteine, alanine, valine, isoleucine, leucine, morpholine, theronine,and N-methylglucamine.

Certain exemplary coformers that can provide a nicotine salt,co-crystal, or co-crystal salt are sugar-based acids (i.e.,monosaccharides with a carboxyl group). Representative types of sugaracids include aldonic acids (e.g., glyceric acid, xylonic acid, gluconicacid, and ascorbic acid), ulosonic acids (e.g., neuraminic acid andketodeoxyoctulosonic acid), uronic acids (e.g., glucuronic acid,galacturonic acid, and iduronic acid), and aldaric acids (e.g., tartaricacid, meso-galactaric acid/mucic acid, and D-glucaric acid/saccharicacid). In one preferred embodiment, the coformer or coformers used toprovide a nicotine salt, co-crystal, or salt co-crystal according to thepresent disclosure is an aldaric acid, and in a particular preferredembodiment, the aldaric acid is mucic acid((2S,3R,4S,5R)-2,3,4,5-tetrahydroxyhexanedioic acid, also referred to asgalactaric or meso-galactaric acid).

Other exemplary coformers that can provide a nicotine co-crystal, salt,or co-crystal salt are polyfunctional aromatic acids. Polyfunctionalaromatic acids often comprise a substituted or unsubstituted phenylgroup as the aromatic component, but can alternatively comprise anotheraromatic moiety, e.g., pyridine, pyrazine, imidazole, pyrazole, oxazole,thiophene, naphthalene, anthracene, and phenanthrene. Substituents onthe optionally substituted aromatic acids may be any type ofsubstituent, including, but not limited to, halo (e.g., Cl, F, Br, andI); alkyl, halogenated alkyl (e.g., CF₃, 2-Br-ethyl, CH₂F, CH₂Cl,CH₂CF₃, or CF₂CF₃); alkenyl, hydroxyl; amino; carboxylate; carboxamido;alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio;sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonategroups. Exemplary polyfunctional aromatic acids can be, for example:substituted and unsubstituted aromatic dicarboxylic acids (e.g.,1,2-benzenedicarboxylic acid (phthalic acid), 1,3-benzenedicarboxylicacid (isophthalic acid), 1,4-benzenedicarboxylic acid (terephthalicacid), 2-iodo-1,3-benzenedicarboxylic acid,2-hydroxy-1,4-benzenedicarboxylic acid, 2-nitro-1,4-benzenedicarboxylicacid, 3-fluoro-1,2-benzenedicarboxylic acid,3-amino-1,2-benzenedicarboxylic acid, 3-nitro-1,2-benzenedicarboxylicacid, 4-bromo-1,3-benzenedicarboxylic acid,4-hydroxy-1,3-benzenedicarboxylic acid, 4-amino-1,2-benzenedicarboxylicacid, 4-nitro-1,2-benzenedicarboxylic acid,4-sulfo-1,2-benzenedicarboxylic acid, 4-amino-1,3-benzenedicarboxylicacid, 5-bromo-1,3-benzenedicarboxylic acid,5-hydroxy-1,3-benzenedicarboxylic acid, 5-amino-1,3-benzenedicarboxylicacid, 5-nitro-1,3-benzenedicarboxylic acid,5-ethynyl-1,3-benzenedicarboxylic acid, 5-cyano-1,3-benzenedicarboxylicacid, 5-nitro-1,3-benzenedicarboxylic acid,2,5-hydroxy-1,4-benzenedicarboxylic acid, and2,3,5,6-tetrafluoro-1,4-benzenedicarboxylic acid; substituted andunsubstituted hydroxybenzoic acids (e.g., 2-hydroxybenzoic acid(salicylic acid), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid,2-methyl-4-hydroxybenzoic acid, 3-tert-butyl-4-hydroxybenzoic acid,4-ethoxy-2-hydroxybenzoic acid, 3-chloro-5-hydroxybenzoic acid,5-chloro-2-hydroxybenzoic acid, 3-bromo-4-hydroxybenzoic acid,3-bromo-5-hydroxybenzoic acid, 4-bromo-2-hydroxybenzoic acid,5-bromo-2-hydroxybenzoic acid, 2-fluoro-5-hydroxybenzoic acid,3-fluoro-4-hydroxybenzoic acid, 3-fluoro-2-hydroxybenzoic acid,3-fluoro-5-hydroxybenzoic acid, 2-fluoro-6-hydroxybenzoic acid,4-fluoro-3-hydroxybenzoic acid, 2-fluoro-4-hydroxybenzoic acid,5-fluoro-2-hydroxybenzoic acid, 2-amino-3-hydroxybenzoic acid,2-amino-5-hydroxybenzoic acid, 3-amino-2-hydroxybenzoic acid,3-amino-4-hydroxybenzoic acid, 3-amino-5-hydroxybenzoic acid,4-amino-2-hydroxybenzoic acid, 4-amino-3-hydroxybenzoic acid,5-amino-2-hydroxybenzoic acid (mesalamine),5-aminomethyl-2-hydroxybenzoic acid, 4-formyl-3-hydroxybenzoic acid,3-formyl-4-hydroxybenzoic acid, 5-(acetylamino)-2-hydroxybenzoic acid),4-nitro-2-hydroxybenzoic acid, 3,5-diethyl-4-hydroxybenzoic acid,3,5-di-tert-butyl-4-hydroxybenzoic acid,3,5-diisopropyl-2-hydroxybenzoic acid, 3,4-dimethoxy-4-hydroxybenzoicacid (syringic acid), 3,5-dichloro-2-hydroxybenzoic acid,3,5-dichloro-4-hydroxybenzoic acid, 3,6-dichloro-2-hydroxybenzoic acid,2,3-difluoro-4-hydroxybenzoic acid, 3,4-difluoro-2-hydroxybenzoic acid,3,5-dibromo-2-hydroxybenzoic acid, 3,5-diodo-2-hydroxybenzoic acid,4-amino-5-chloro-2-hydroxybenzoic acid, 3,5-dinitro-2-hydroxybenzoicacid, 2,4,6-tribromo-2-hydroxybenzoic acid,2,3,5,6-tetrafluoro-4-hydroxybenzoic acid, and2,3,4,5-tetrafluoro-6-hydroxybenzoic acid);

substituted and unsubstituted dihydroxybenzoic acids (e.g.,2,3-dihydroxybenzoic acid (pyrocatechuic acid/hypogallic acid),2,4-dihydroxybenzoic acid (β-resorcylic acid), 2,5-dihydroxybenzoic acid(gentisic acid/hydroquinonecarboxylic acid), 2,6-dihydroxybenzoic acid(γ-resorcylic acid), 3,4-dihydroxybenzoic acid (protocatechuic acid),3,5-dihydroxybenzoic acid (α-resorcylic acid),4-hydroxy-3-methoxybenzoic acid (vanillic acid),6-methyl-2,4-dihdroxybenzoic acid (orsellenic acid),4-bromo-3,5-dihydroxybenzoic acid, 5-bromo-2,4-dihydroxybenzoic acid,5-bromo-3,4-dihydroxybenzoic acid, 6-carboxymethyl-2,3-dihydroxybenzoicacid, 3,5-dibromo-2,4-dihydroxybenzoic acid,3,5-dichloro-2,6-dihydroxybenzoic acid, and5-amino-3-chloro-2,4-dihydroxybenzoic acid); and

substituted and unsubstituted trihydroxybenzoic acids (e.g.,2,3,4-trihydroxybenzoic acid, 2,4,5-trihydroxybenzoic acid,2,4,6-trihydroxybenzoic acid (phloroglucinol carboxylic acid), and3,4,5-trihydroxybenzoic acid (gallic acid)).

substituted and unsubstituted aromatic tricarboxylic acids (e.g.,1,2,3-benzenetricarboxylic acid, 1,2,4-benzenetricarboxylic acid(trimellitic acid); and

substituted and unsubstituted aromatic tetracarboxylic acids (e.g.,1,2,3,4-benzenetetracarboxylic acid (mellophanic acid) and1,2,4,5-benzenetetracarboxylic acid (pyromellitic acid).

Other coformers useful in certain embodiments are flavor acids,including but not limited to, 3-hydroxy-2-oxopropionic acid;2-oxobutyric acid (2-ketobutyric acid), 3-methyl-2-oxobutanoic acid;3-methyl-2-oxopentanoic acid; 4-methyl-2-oxopentanoic acid; and2-oxopentanedioic acid. Additional coformers can have higher molecularweights, such as 2-oxo-3-phenylpropionic acid; 5-oxooctanoic acid; and5-oxodecanoic acid.

It is noted that certain coformers as described herein may contain oneor more chiral centers, which may be either of the (R) or (S)configuration, or which may comprise a mixture thereof. As a result,various diasteromeric nicotine salts, co-crystals and salt co-crystalsmay be provided according to the present disclosure. The inventionincludes such diastereomers, either individually, or admixed in anyproportions. Certain coformers as described herein may be geometricisomers, including but not limited to cis and trans isomers across adouble bond. The invention includes all nicotine salts, co-crystals, andsalt co-crystals prepared with such isomers, which may be provided inthe form of pure isomers or in admixture with other isomers.

The method(s) by which the nicotine salts, co-crystals, and saltco-crystals described herein can be produced can vary. In someembodiments, no solvent (or a minimal amount of solvent) is used toprepare the nicotine salts, co-crystals, and salt co-crystals. Althoughin so-called “solventless” methods, a solvent is commonly not used, itis noted that one or more solvents may optionally be added (typically ina small amount) to the mixture to facilitate the formation of a nicotinesalt, co-crystal, or salt co-crystal. In certain embodiments, thecomponents (i.e., the nicotine and the one or more coformers) arecombined in the absence of a solvent to form a slurry. Solids comprisingnicotine salts, co-crystals, and/or salt co-crystals may be isolatedtherefrom via common methods (e.g., filtration). The slurry may beoptionally heated such that the nicotine and one or more coformersinteract in melted form to produce a salt, co-crystal, or saltco-crystal. In certain embodiments, physical methods are used to combinethe components (i.e., the nicotine and the one or more coformers). Forexample, the nicotine and the coformer(s) can be ground togethermechanically (e.g., using a mortar and pestle, ball mill, or vibratorymill).

In certain embodiments, a combination of nicotine and a coformer in agiven solvent (or solvents) and evaporation of that solvent can providethe desired nicotine salt, co-crystal, or salt co-crystal. Typically, insuch methods, the nicotine and coformer are provided in stoichiometricamounts (i.e., no excess nicotine or coformer is added). In suchmethods, selection of solvent is important, as the solvent (or solvents)in which the reaction is conducted can impact the intermolecularinteractions. The evaporation of solvent can be done at a controlledrate (e.g., slowly) to encourage the preparation of a single nicotinesalt, co-crystal, or salt co-crystal crystal for characterization. Forexample, the evaporation of solvent may be effected over the course ofhours, days, weeks, or months.

In some embodiments, a combination of nicotine and a coformer in a givensolvent (or solvents) and addition of a non-solvent can provide thedesired nicotine salt, co-crystal, or salt co-crystal. Exemplarysolvents and non-solvents that can be used for the preparation ofnicotine salts, co-crystals, and salt co-crystals include, but are notlimited to, water, alcohols (e.g., methanol, ethanol, n-butanol,isopropanol), ethers (e.g., diethyl ether, petroleum ether), ethylacetate, acetone, tetrahydrofuran, methylene chloride, chloroform,alkanes (e.g., pentane, hexane, heptane, octane, nonane, cyclohexane),benzene, toluene, 1,4-dioxane, and combinations thereof. In someembodiments, nicotine salts, co-crystals, and salt co-crystals can beprepared in supercritical fluids.

In other embodiments, the desired nicotine salt, co-crystal, or saltco-crystal can be prepared by freeze drying and subsequent maturation ofa solution of nicotine and one or more coformers. For example, asolution may be prepared, frozen, and lyophilized to remove the solvent.A maturation solvent can then be added and the resulting solids can beobtained by common methods (e.g., filtration). Maturation solventsinclude, but are not limited, the types of solvents noted above.

The method of production of nicotine salts, co-crystals, and saltco-crystals as described herein may, in some embodiments, employ anexcess of the coformer component. In such embodiments, it canadvantageously be possible to purify the resulting salt, co-crystal, orsalt co-crystal by removing excess coformer therefrom (i.e., thatcoformer which is not part of the structure of the salt, co-crystal, orsalt co-crystal). Exemplary means for salt, co-crystal, or saltco-crystal formation that may, in certain embodiments, be applicable forthe preparation of the nicotine salts, co-crystals, and salt co-crystalsdescribed herein are disclosed, for example, in U.S. Pat. No. 8,513,236to Schultheiss et al.; U.S. Pat. No. 8,470,832 to George et al.; U.S.Pat. No. 8,466,280 to Grunenberg et al.; U.S. Pat. No. 8,415,507 toSchultheiss et al.; U.S. Pat. No. 8,350,085 to Childs; U.S. Pat. No.8,241,371 to Hanna et al.; U.S. Pat. No. 8,212,079 to Childs; U.S. Pat.No. 8,173,625 to Brittain et al; U.S. Pat. No. 8,163,790 to Childs; U.S.Pat. No. 8,197,592 to Imamura et al.; U.S. Pat. No. 8,058,437 to Baueret al.; U.S. Pat. No. 7,935,817 to Blazecka et al.; U.S. Pat. No.7,927,613 to Almarsson et al.; U.S. Pat. No. 7,452,555 to Childs; U.S.Pat. No. 7,008,742 to Molaire; U.S. Pat. App. Pub. Nos. 2013/0203806 toChorlton et al.; 2013/0072440 to Dokou et al.; 2013/0040970 to Cosgroveet al.; 2012/0258170 to Kruthiventi et al.; 2012/0028998 to Sansone etal.; 2012/0028930 to Kalofonos et al.; 2012/0022117 to Gruss et al.;2011/0257340 to Childs; 2011/0251426 to Hanna et al.; 2011/0236478 toDokou et al.; 2011/0152266 to Grunenberg et al.; 2010/0204204 toZaworotko et al; 2008/0280858 to Hanna et al., 2007/0287194 to Childs etal.; 2003/0224006 to Zaworotko et al.; and 2002/0048610 to Cima et al.,which are all incorporated herein by reference in their entireties.Other references that provide exemplary means for the formation ofcertain nicotine salts include M. Dezelic and B. Nikolin, “NicotineCompounds with Aromatic Acids. Part II.,” Glasnik Drustva HemicaraTechnol. N. R. Bosne I Hercegovine, Sarajevo, 10 (1961) 55-62 and M.Dezelic and D. Tomic, “Nicotine Compounds with Aromatic Acids,” Kem.Vjestnik 17 (1943):39-57, which are incorporated herein by reference.

For the preparation of nicotine mucate, in one embodiment, the salt isprovided by combining the acid and nicotine in the absence of solvent.In some embodiments, an excess of nicotine is added to the reactionmixture and, advantageously, excess nicotine is removed (e.g., by vacuumand/or by washing/filtration, such as with THF, heptane, and/or EtOAc).

For the preparation of the novel polymorphic form of nicotine4-acetamidobenzoate described herein, in one embodiment, the salt isprovided by combining the acid and nicotine in the absence of solvent.For example, in one embodiment, 4-acetamidobenzoic acid is suspended inthe minimum amount of nicotine required to produce a mobile slurry,which is stirred/shaken to form the nicotine salt. In anotherembodiment, a solvent (e.g., THF) is used to facilitate salt formation.For example, 4-acetamidobenzoic acid can be dissolved in THF, nicotinecan be added thereto, and the resulting mixture can be stirred/shaken toproduce the salt. The solvent can be removed (e.g., by evaporation) toprovide the desired nicotine 4-acetamidobenzoate form. In someembodiments, the solid is washed, e.g., with THF, heptane, and/or EtOAc.

For the preparation of the novel polymorphic form of nicotine gentisatedescribed herein, in one embodiment, the salt is provided by combiningthe acid and nicotine in the absence of solvent. For example, in oneembodiment, gentisic acid is suspended in the minimum amount of nicotinerequired to produce a mobile slurry, which is stirred/shaken to form thenicotine salt. In another embodiment, a solvent (e.g., THF) is used tofacilitate salt formation. For example, 4-acetamidobenzoic acid can bedissolved in THF, nicotine can be added thereto, and the resultingmixture can be stirred/shaken to produce the salt. The solvent can beremoved (e.g., by evaporation) to provide the desired nicotine4-acetamidobenzoate. In some embodiments, the solid is washed, e.g.,with THF and/or heptane.

For the preparation of the nicotine 3,5-dihydroxybenzoate describedherein, in one embodiment, the salt is provided by combining the acidand nicotine in a solvent (e.g., THF or acetone). For example,3,5-dihydroxybenzoic acid can be dissolved in THF or acetone, followedby nicotine; the resulting mixture can be stirred/shaken to give thesolid salt. The solvent can be removed (e.g., by evaporation) andoptionally washed as described above (e.g., with heptane) to provide thedesired 3,5-dihydroxybenzoate. In certain embodiments, this methodprovides the anhydrous form, which can readily be converted to ahydrated form, such as the dihydrate form described herein (e.g., byexposing the anhydrous form to elevated humidity levels, e.g., 96%relative humidity at 25° C. for 16 h). It is understood that varyingamounts of humidity, temperature, and time may provide the hydrated(e.g., dihydrate) form.

For the preparation of nicotine 2,3-dihydroxybenzoate as describedherein, in one embodiment, the salt can be prepared in neat nicotine (inthe absence of solvent). In another embodiment, a solvent can beemployed. For example, 2,3-dihydroxybenzoic acid can be dissolved inTHF, followed by nicotine; the resulting mixture can be stirred/shakento give the solid salt. The solvent can be removed (e.g., byevaporation) and optionally washed as described above (e.g., withheptane) to provide the desired nicotine 2,3-dihydroxybenzoate.

For the preparation of the nicotine 1-hydroxy-2-naphthoate formdescribed herein, in one embodiment, the salt can be prepared in neatnicotine (in the absence of solvent). In another embodiment, a solventcan be employed. For example, 1-hydroxy-2-naphthoic acid can bedissolved in THF, followed by nicotine; the resulting mixture can bestirred/shaken to give the solid salt. The solvent can be removed (e.g.,by evaporation) and optionally washed as described above (e.g., withheptane) to provide the desired polymorphic crystalline form of nicotine1-hydroxy-2-naphthoate.

Desirably, single crystal x-ray diffraction (SCXRD) can be used in someembodiments to determine the makeup of the solids (i.e., the nicotinesalts, co-crystals, and salt co-crystals). However, suitable, x-rayquality crystals cannot always be readily produced. Therefore, a varietyof other solid state spectroscopic techniques can be used including, butnot limited to, x-ray powder diffraction (MOD), Raman spectroscopy, FTIRspectroscopy, vibrational spectroscopy, polarized light microscopy(PLM), and solid state NMR. The nicotine salts, co-crystals, and saltco-crystals described herein may be further characterized, for example,using such techniques as ¹³C NMR and ¹H NMR (in a suitable solvent,e.g., in D₂O or DMSO-d₆) to evaluate the chemical structure, GravimetricVapor Sorption (GVS) to evaluate the hygroscopicity, thermogravimetricanalysis (TGA) and differential scanning calorimetry (DSC) to evaluatethe thermal properties, and/or chromatography (e.g., HPLC) in a suitablesolvent to evaluate the purity. Products as described herein can befurther analyzed via Karl Fischer Titration (KF) to determine the watercontent.

It is noted that, in certain cases, it is difficult to distinguishbetween co-crystals and salts. Typically, distinguishing a salt from aco-crystal requires evidence of proton transfer, which may not bestraightforward to identify even with single crystal x-ray diffraction.In other terms, distinguishing a salt from a co-crystal generallyrequires evidence of ionic interactions, as opposed to merely non-ionicinteractions. Accordingly, although the novel compositions describedherein are described as salts, it is noted that in some embodiments, itmay not be known whether a given product exists in salt, co-crystal, orsalt co-crystal form or in some type of intermediate form (e.g., whereinthe proton has not been transferred to a basic site, but may reside inspace between the donor coformer and acceptor).

The nicotine salts, co-crystals, and salt co-crystals described hereincan be incorporated into various products, including tobacco-containingproducts. The important characteristics of nicotine salts, co-crystals,and salt co-crystals for use in different types of products vary, aswill be discussed in detail below.

The nicotine salts, co-crystals, and salt co-crystals provided hereincan, in some embodiments, be used as compositions in the manufacture ofsmoking articles. For example, salts, co-crystals, and salt co-crystalsprepared in accordance with the present invention can be mixed withcasing materials and applied to tobacco as a casing ingredient or as atop dressing. Still further, salts, co-crystals, and salt co-crystals ofthe present disclosure can be incorporated into a cigarette filter(e.g., in the filter plug, plug wrap, or tipping paper) or incorporatedinto cigarette wrapping paper, preferably on the inside surface, duringthe cigarette manufacturing process. See, for example, the descriptionand references related to tobacco isolates used in smoking articles setforth in US Pat. Pub. No. 2012/0192880 to Dube et al., which isincorporated by reference herein. Representative tobacco blends,non-tobacco components, and representative cigarettes manufacturedtherefrom are also set forth in the Dube et al. reference noted above.

Typically, the amount of nicotine salt, co-crystal, or salt co-crystalincorporated into a smoking article is that amount sufficient to providethe desired amount of free nicotine in the mainstream smoke producedtherefrom. For example, in some embodiments, the smoking article mayprovide nicotine in an amount of about 0.1 mg to about 10 mg, about 0.5mg to about 9 mg, or about 1 mg to about 8 mg. Accordingly, the amountof nicotine salt, co-crystal, or salt co-crystal incorporated into thesmoking article can be, for example, that amount sufficient to producethese amounts of nicotine when the article is used.

Referring to FIG. 19, there is shown a smoking article 10 in the form ofa cigarette and possessing certain representative components of asmoking article that can contain the formulation of the presentinvention. The cigarette 10 includes a generally cylindrical rod 12 of acharge or roll of smokable filler material (e.g., about 0.3 g to about1.0 g of smokable filler material such as tobacco material) contained ina circumscribing wrapping material 16. The rod 12 is conventionallyreferred to as a “tobacco rod.” The ends of the tobacco rod 12 are opento expose the smokable filler material. The cigarette 10 is shown ashaving one optional band 22 (e.g., a printed coating including afilm-forming agent, such as starch, ethylcellulose, or sodium alginate)applied to the wrapping material 16, and that band circumscribes thecigarette rod in a direction transverse to the longitudinal axis of thecigarette. The band 22 can be printed on the inner surface of thewrapping material (i.e., facing the smokable filler material), or lesspreferably, on the outer surface of the wrapping material.

At one end of the tobacco rod 12 is the lighting end 18, and at themouth end 20 is positioned a filter element 26. The filter element 26positioned adjacent one end of the tobacco rod 12 such that the filterelement and tobacco rod are axially aligned in an end-to-endrelationship, preferably abutting one another. Filter element 26 mayhave a generally cylindrical shape, and the diameter thereof may beessentially equal to the diameter of the tobacco rod. The ends of thefilter element 26 permit the passage of air and smoke therethrough.

A ventilated or air diluted smoking article can be provided with anoptional air dilution means, such as a series of perforations 30, eachof which extend through the tipping material and plug wrap. The optionalperforations 30 can be made by various techniques known to those ofordinary skill in the art, such as laser perforation techniques.Alternatively, so-called off-line air dilution techniques can be used(e.g., through the use of porous paper plug wrap and pre-perforatedtipping paper). The salts of the invention can be incorporated withinany of the components of a smoking article, including but not limitedto, as a component of the tobacco charge, as a component of the wrappingpaper (e.g., included within the paper or coated on the interior orexterior of the paper), as an adhesive, as a filter element component,and/or within a capsule located in any region of the smoking article.

The temperature at which nicotine, the coformer component (orcomponents), and any degradation products thereof are released from anicotine salt, co-crystal, or salt co-crystal can be a relevantconsideration in the context of smoking articles. It is typicallyimportant that nicotine is released from the salt, co-crystal, or saltco-crystal (i.e., that the nicotine transfers to the mainstream smokeand is delivered to the user) at the burn temperature of the smokingarticle. It can also be important in some embodiments to ensure thatcertain undesirable coformers and/or degradation products thereof arenot transferred to the mainstream smoke (and delivered to the user). Therelevant temperature may vary slightly, depending upon the specificlocation(s) of the salt, co-crystal, or salt co-crystal within thesmoking article. For example, in certain embodiments, the temperature atwhich a smoking article burns (and thus the temperature to which thesalt is exposed) can be between at least about 100° C., at least about200° C., or at least about 500° C., including between about 100° C. andabout 500° C. in certain regions of a smoking article and between about600° C. and about 900° C. in other regions of a smoking article. Theseconsiderations can impact selection of the salts, co-crystals, or saltco-crystals that are suitable for a particular application.

In other embodiments, the nicotine salts, co-crystals, and saltco-crystals disclosed herein can be incorporated within smokelesstobacco products. Representative smokeless tobacco compositionsaccording to the present invention can have various types of formats andconfigurations, and as a result, the character, nature, behavior,consistency, shape, form, size and weight of the composition can vary.In some embodiments, the nicotine salts, co-crystals, and saltco-crystals disclosed herein can be incorporated into smokeless tobaccoproducts, such as loose moist snuff (e.g., snus); loose dry snuff;chewing tobacco; pelletized tobacco pieces; extruded or formed tobaccostrips, pieces, rods, cylinders or sticks; finely divided groundpowders; finely divided or milled agglomerates of powdered pieces andcomponents; flake-like pieces; molded tobacco pieces; gums; rolls oftape-like films; readily water-dissolvable or water-dispersible films orstrips; meltable compositions; lozenges; pastilles; or capsule-likematerials possessing an outer shell and an inner region. The shape of arepresentative composition can be generally spherical, cylindrical(e.g., ranging from the general shape of a flattened disc to the generalshape of a relatively long, slender stick), helical, obloid, square,rectangular, or the like; or the composition can have the form of abead, granular powder, crystalline powder, capsule, film, strip, gel, orthe like. The shape of the composition can resemble a wide variety ofpill, tablet, lozenge, capsule, and caplet types of products. Varioustypes of smokeless tobacco products are described or referenced in USPat. Pub. Nos. 2013/0206150 to Duggins et al.; 2013/0074855 to Holton,Jr.; 2012/0118310 to Cantrell et al.; 2012/0138073 to Cantrell et al.;2012/0138074 to Cantrell et al.; and 2012/0152265 to Dube et al., whichare all incorporated herein by reference.

Referring to FIG. 20, a representative snus type of tobacco productcomprising one or more nicotine salts, co-crystals, or salt co-crystalsaccording to the present disclosure is shown. In particular, FIG. 20illustrates a smokeless tobacco product 40 having a water-permeableouter pouch 42 containing a smokeless tobacco composition 44. Any of thecomponents of the tobacco product can comprise one or more nicotinesalts, co-crystals, or salt co-crystals, according to the presentdisclosure (e.g., the interior or exterior of the pouch lining or aportion of the smokeless tobacco composition contained therein).

Other exemplary smokeless tobacco products into which the salts,co-crystals, and salt co-crystals described herein can be incorporatedcan have the form of a gum, lozenge, tablet, microtab, or othertablet-type product. See, for example, the types of nicotine-containinglozenges, lozenge formulations, lozenge formats and configurations,lozenge characteristics and techniques for formulating or manufacturinglozenges set forth in U.S. Pat. No. 4,967,773 to Shaw; U.S. Pat. No.5,110,605 to Acharya; U.S. Pat. No. 5,733,574 to Dam; U.S. Pat. No.6,280,761 to Santus; U.S. Pat. No. 6,676,959 to Andersson et al.; U.S.Pat. No. 6,248,760 to Wilhelmsen; and U.S. Pat. No. 7,374,779; US Pat.Pub. Nos. 2013/0074855 and 2013/0078307 to Holton, Jr.; 2001/0016593 toWilhelmsen; 2004/0101543 to Liu et al.; 2006/0120974 to Mcneight;2008/0020050 to Chau et al.; 2009/0081291 to Gin et al.; and2010/0004294 to Axelsson et al.; and 2013/0312774 to Holton, Jr., whichare all incorporated herein by reference.

One representative type of smokeless tobacco product comprising one ormore of the nicotine salts, co-crystals, or salt co-crystals describedherein is a lozenge, e.g., as substantially described in US Pat. App.Pub. Nos. 2013/0312774, 2013/0074856, and 2013/0074855, all to Holton,Jr., which are incorporated herein by reference. Such lozenges cancomprise, in addition to one or more nicotine salts, co-crystals, orsalt-co-crystals, a majority of one or more sugar alcohols (e.g.,isomalt and maltitol syrup), e.g., in an amount of at least about 50% byweight, at least about 70% by weight, at least about 80% by weight, orat least about 90% by weight. Other ingredients of particular interestin such lozenge products include, but are not limited to, salts (e.g.,NaCl), sweeteners (e.g., sucralose), and one or more flavorings.

The amount of nicotine salt, co-crystal, or salt co-crystal incorporatedwithin a smokeless tobacco composition can vary and can be dependent, inpart, on the specific type of smokeless tobacco composition. Clearly,the amount of a given nicotine salt, co-crystal, or salt co-crystal tobe incorporated within a product will depend on the desired nicotinecontent of that product, and can be calculated based on the mass of thecoformer and the stoichiometry of the salt, co-crystal, or saltco-crystal. Exemplary amounts include from about 0.1% by weight of theconsumable material to about 10% by weight of the consumable orinhalable material. For example, for a lozenge, the amount of nicotinesalt, co-crystal, or salt co-crystal is at least about 0.5%, generallyat least about 1%, often at least about 1.5%, often at least about 2%,often at least about 2.5%, and frequently at least about 3% by weight ofthe product, e.g., about 0.5% to about 10%, including about 1% to about5% by weight of the product. The amount of nicotine salt, co-crystal, orsalt co-crystal can be determined based on the desired nicotine contentin the lozenge.

Various other substances can be added to the smokeless tobaccocompositions comprising the nicotine salts, co-crystals, or saltco-crystals of the present invention. For example, excipients such asfillers or carriers for active ingredients (e.g., calcium polycarbophil,microcrystalline cellulose, hydroxypropylcellulose, sodiumcarboxymethylcellulose, cornstarch, silicon dioxide, calcium carbonate,lactose, and starches including potato starch, maize starch, etc.),thickeners, film formers and binders (e.g., hydroxypropyl cellulose,hydroxypropyl methylcellulose, acacia, sodium alginate, gum arabic,lecithin, xanthan gum and gelatin), antiadherents (e.g., talc), glidants(e.g., colloidal silica), humectants (e.g., glycerin), preservatives andantioxidants (e.g., sodium benzoate and ascorbyl palmitate), surfactants(e.g., polysorbate 80), dyes or pigments (e.g., titanium dioxide or D&CYellow No. 10), and lubricants or processing aids (e.g., calciumstearate or magnesium stearate) are added to the compositions in certainembodiments. Other exemplary types of ingredients include salts (e.g.,sodium chloride, potassium chloride, sodium citrate, potassium citrate,sodium acetate, potassium acetate, and the like), natural sweeteners(e.g., fructose, sucrose, glucose, maltose, vanillin, ethylvanillinglucoside, mannose, galactose, lactose, and the like), artificialsweeteners (e.g., sucralose, saccharin, aspartame, acesulfame K, neotameand the like), pH adjusters or buffering agents (e.g., metal hydroxides,preferably alkali metal hydroxides such as sodium hydroxide andpotassium hydroxide, and other alkali metal buffers such as metalcarbonates, preferably potassium carbonate or sodium carbonate, or metalbicarbonates such as sodium bicarbonate, and the like), effervescingmaterials such as certain acid/base combinations, oral care additives(e.g., thyme oil, eucalyptus oil, and zinc), preservatives (e.g.,potassium sorbate, and the like), syrups (e.g., honey, high fructosecorn syrup, and the like), and mixtures thereof. In certain embodiments,the smokeless tobacco composition can include lipid components thatprovide a meltable composition that melts (as opposed to merelydissolving) in the oral cavity, such as compositions set forth in USPat. Pub. No. 2012/0037175 to Cantrell et al., which is incorporated byreference herein. Exemplary encapsulated additives that can be includedwithin the smokeless tobacco products disclosed herein are described,for example, in WO 2010/132444 to Atchley, which has been previouslyincorporated by reference herein. See also, the smokeless tobaccoingredients set forth in US Pat. Pub. Nos. 2012/0055494 to Hunt et al.and 2012/0199145 to Byrd et al., which are incorporated by referenceherein.

The manners and methods used to formulate and manufacture the smokelesstobacco product can vary. Ingredients, including the nicotine salts,co-crystals, or salt co-crystals described herein, can be combined andprocessed into the desired composition by techniques such as extrusion,compression, molding, spraying, and the like. It is noted that certainconsiderations noted above for electronic smoking articles are notrelevant in the context of a smokeless tobacco product. For example,nicotine salts, co-crystals, or salt co-crystals that are useful insmokeless tobacco products need not transfer to aerosol form at a giventemperature. In smokeless tobacco products, the main consideration isthat the nicotine salt, co-crystal, or salt co-crystal contained thereincan provide nicotine when the smokeless tobacco product is placed in themouth of the user (i.e., at some point during residence of the smokelesstobacco product in the mouth of the user). Accordingly, certain nicotinesalts, co-crystals, or salt co-crystals that are useful for one type oftobacco product may not be useful for others.

In certain embodiments, the nicotine salts, co-crystals, and saltco-crystals provided according to the present disclosure areincorporated within electronic smoking articles. An exemplary embodimentof an electronic smoking article 200 incorporating a nicotine salt,co-crystal, or salt co-crystal according to the present disclosure isshown in FIG. 21. As illustrated therein, a control body 202 can beformed of a housing 201 that can include a control component 206, a flowsensor 208, a battery 210, and an LED 212. The electronic smokingarticle also may comprise a cartridge 204 that can be formed of ahousing 203 enclosing a reservoir 244 that is in fluid communicationwith a transport element 236 adapted to wick or otherwise transport anaerosol precursor composition stored in the reservoir to a heater 234(e.g., a resistive heating wire that may be coiled around at least aportion of the transport element). Exemplary reservoirs and transportelements are disclosed in US Pat. Pub. No. 2014/0261487 to Chapman etal., and exemplary heaters are disclosed in US Pat. Pub. No.2014/0157583 to Ward et al., the disclosures of which are incorporatedherein by reference in their entireties. An opening 228 may be presentin the cartridge housing 203 at a mouthend 205 thereof to allow foregress of formed aerosol from the cartridge 204. Such components arerepresentative of the components that may be present in a control bodyand/or cartridge and are not intended to limit the scope of componentsthat are encompassed by the present disclosure.

The cartridge 204 may be adapted to engage the control body 202 througha press-fit engagement between the control body projection 224 and thecartridge receptacle 240. Such engagement can facilitate a stableconnection between the control body 202 and the cartridge 204 as well asestablish an electrical connection between the battery 210 and controlcomponent 206 in the control body and the heater 234 in the cartridge.Other types of connections (e.g., a screw thread connection) also areencompassed. The electronic smoking article 200 may be adapted for airintake, which may be provided in a coupler as described, for example, inUS Pat. Pub. No. 2014/0261408 to DePiano et al., the disclosure of whichis incorporated herein by reference in its entirety. The cartridge 204also may include one or more electronic components 250, which mayinclude an IC, a memory component, a sensor, or the like. The electroniccomponent 250 may be adapted to communicate with the control component206 so as to provide an input. See, for example, US Pat. Pub. Nos.2014/0096781 to Sears et al. and 2014/0096782 to Ampolini et al., thedisclosures of which are incorporated herein by reference in theirentirety.

The electronic smoking article can encompass a variety of combinationsof components useful in forming an electronic aerosol delivery device.Reference is made for example to the following: a reservoir and heatersystem for controllable delivery of multiple aerosolizable materialsdisclosed in US Pat. Pub. No. 2014/0000638 to Sebastian et al.;microheaters as disclosed in US Pat. Pub. No. 2014/0060554 to Collett etal.; carbon-based cartridges and components thereof, as disclosed USPat. Pub. No. 2013/0255702 to Griffith, Jr. et al.; single-usecartridges as disclosed in US Pat. Pub. No. 2014/0060555 to Chang etal.; aerosol precursor transport elements, such as disclosed in US Pat.Pub. No. 2014/0209105 to Sears et al.; charging components, such as anadaptor disclosed in US Pat. Pub. No. 2014/0261495 to Novak, III et al.;vibration components, such as disclosed in US Pat. Pub. No. 2015/0020825to Galloway et al.; and batteries, such as disclosed in U.S. Pat. Pub.No. 2010/0028766 to Peckerar et al.

Representative types of aerosol precursor components and formulationsalso are set forth and characterized in U.S. Pat. No. 7,217,320 toRobinson et al. and U.S. Pat. Pub. Nos. 2013/0008457 to Zheng et al.;2013/0213417 to Chong et al.; 2014/0060554 to Collett et al.;2015/0020823 to Lipowicz et al.; and 2015/0020830 to Koller, as well asWO 2014/182736 to Bowen et al, the disclosures of which are incorporatedherein by reference. Other aerosol precursors that may be employedinclude the aerosol precursors that have been incorporated in the VUSE®product by R. J. Reynolds Vapor Company, the BLU™ product by LorillardTechnologies, the MISTIC MENTHOL product by Mistic Ecigs, and the VYPEproduct by CN Creative Ltd. Also desirable are the so-called “smokejuices” for electronic cigarettes that have been available from JohnsonCreek Enterprises LLC.

In certain embodiments, the aerosol precursor comprises a nicotine salt,co-crystal, or salt co-crystal as disclosed herein. In one embodiment,the aerosol precursor composition can comprise, for example, apolyhydric alcohol (e.g., glycerin, propylene glycol, or a combinationthereof), water, a nicotine salt, co-crystal, or salt co-crystal asdescribed herein, and a flavorant (e.g., menthol). Exemplary flavoringagents include vanillin, ethyl vanillin, cream, tea, coffee, fruit(e.g., apple, cherry, strawberry, peach and citrus flavors, includinglime and lemon), maple, menthol, mint, peppermint, spearmint,wintergreen, nutmeg, clove, lavender, cardamom, ginger, honey, anise,sage, cinnamon, sandalwood, jasmine, cascarilla, cocoa, licorice, andflavorings and flavor packages of the type and character traditionallyused for the flavoring of cigarette, cigar, and pipe tobaccos. Syrups,such as high fructose corn syrup, also can be employed. Flavoring agentsalso can include acidic or basic characteristics (e.g., organic acids,such as levulinic acid, succinic acid, and pyruvic acid). Representativetypes of aerosol precursor compositions are set forth in U.S. Pat. No.4,793,365 to Sensabaugh, Jr. et al.; U U.S. Pat. No. 5,101,839 to Jakobet al.; U.S. Pat. Pub. No. 2013/0008457 to Zheng et al.; and Chemicaland Biological Studies on New Cigarette Prototypes that Heat Instead ofBurn Tobacco, R. J. Reynolds Tobacco Company Monograph (1988). Thedisclosures of all of the foregoing documents are incorporated herein byreference in their entireties.

One or more acid components can be included within the aerosolprecursor, e.g., to modify the sensory characteristics of the aerosolprecursor and the aerosol produced therefrom. Organic acids particularlymay be incorporated into the aerosol precursor to affect the flavor,sensation, and/or organoleptic properties of nicotine. Such organicacids can be included in the aerosol precursor with nicotine in varyingamounts ranging from greater than equimolar to less than equimolar(based on total organic acid content) with the nicotine. A range oforganic acids can be used in accordance with such embodiments, e.g., asset forth in Perfetti, Beitrage Tabakforschung Int., 12, 43-54 (1983),which is incorporated herein by reference. Certain exemplary organicacids that may be useful include, but are not limited to, such acids astartaric acid, ascorbic acid, fumaric acid, citric acid, malic acid,lactic acid, aspartic acid, salicylic acid, 4-amino salicylic acid,N-acetyl-4-aminosalicylic acid, p-toluenesulfonic acid, succinic acid,pyruvic acid, formic acid, acetic acid, propionic acid, isobutyric acid,butyric acid, alpha-methylbutyric acid, 2-ketobutyric acid, isovalericacid, beta-methylvaleric acid, caproic acid, 2-furoic acid, phenylaceticacid, heptanoic acid, octanoic acid, nonanoic acid, oxalic acid, malonicacid, glycolic acid, levulinic acid, 4-aminobenzoic acid,4-acetamidobenzoic acid, 3-hydroxybenzoic acid, 2,5-dihydroxybenzoicacid, 2,3-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid,3,4-dihydroxybenzoic acid, vanillic acid, mucic acid, cyclamic acid,benzenesulfonic acid, 2-hydroxyethanesulfonic acid,1-hydroxy-2-naphthoic acid, ketoglutaric acid, D-glucuronic acid, maleicacid, glutamic acid, L-pyroglutamic acid, nicotinic acid, isonicotinicacid, gallic acid, phthalic acid, mandelic acid, hippuric acid, cinnamicacid, adipic acid, orotic acid, sorbic acid, clofibric acid, tauricacid, and combinations of two or more such organic acids. By using anicotine salt, co-crystal, or salt co-crystal in place of nicotine, itmay be possible in certain embodiments to reduce and or eliminate theamount of acid advantageously incorporated within the aerosol precursor.

The amount of aerosol precursor composition that is used within thesmoking article is such that the article exhibits acceptable sensory andorganoleptic properties, and desirable performance characteristics. Forexample, it is highly preferred that sufficient aerosol precursorcomposition components, such as glycerin and/or propylene glycol, beemployed in order to provide for the generation of a visible mainstreamaerosol that in many regards resembles the appearance of tobacco smoke.Typically, the amount of aerosol-generating material incorporated intothe smoking article is in the range of about 1.5 g or less, about 1 g orless, or about 0.5 g or less. The amount of aerosol precursorcomposition can be dependent upon factors such as the number of puffsdesired per cartridge used with the smoking article. It is desirable forthe aerosol-generating composition not to introduce significant degreesof unacceptable off-taste, filmy mouth-feel, or an overall sensoryexperience that is significantly different from that of a traditionaltype of cigarette that generates mainstream smoke by burning tobacco cutfiller. The selection of the particular aerosol-generating material andreservoir material, the amounts of those components used, and the typesof tobacco material used, can be altered in order to control the overallchemical composition of the mainstream aerosol produced by the smokingarticle.

Typically, the amount of nicotine incorporated into an aerosol precursorof an electronic smoking article is that amount sufficient to providethe desired amount of free nicotine in the aerosol produced therefrom.For example, the article may provide nicotine in an amount of about 0.01mg to about 0.5 mg, about 0.05 mg to about 1 mg, about 0.08 mg to about0.5 mg, about 0.1 mg to about 0.3 mg, or about 0.15 mg to about 0.25 mgper puff on the article. Accordingly, the amount of nicotine salt,co-crystal, or salt co-crystal incorporated into the aerosol precursorcan be, for example, that amount sufficient to produce these amounts ofnicotine when the article is used.

When the nicotine salts, co-crystals, or salt co-crystals describedherein are used in electronic smoking articles, the temperature at whichnicotine is released into aerosol form from the salt, co-crystal, orsalt co-crystal is an important consideration. It is typically importantthat nicotine is released from the salt, co-crystal, or salt co-crystal(i.e., that the nicotine transfers to aerosol form) at the operatingtemperature of the electronic smoking articles. Although not intended tobe limiting, exemplary operating temperatures of electronic smokingarticles are within the range of about 100° C. to about 500° C. (e.g.,about 120° C. to about 300° C.). Accordingly, selection of anappropriate nicotine salt, co-crystal, or salt co-crystal forincorporation into such products can depend, in part, on thecharacteristics of the bond between the nicotine and the coformer andthe volatility of the salt, co-crystal, or salt co-crystal. For example,nicotine citrate may not be a good salt for an electronic smokingarticle because it is not sufficiently volatile.

Furthermore, in some embodiments, the temperature at which the coformercomponent (or components) is released from a nicotine salt, co-crystal,or salt co-crystal can be a relevant consideration. As it may not beadvantageous for certain coformers (e.g., certain acids) to be presentin the aerosol (and delivered to the user), it can be important toconsider the temperature at which not only the nicotine, but also thecoformer of the nicotine salt, co-crystal, or salt co-crystal transfersto aerosol form. In other embodiments, the coformer(s) of a givennicotine salt, co-crystal, or salt co-crystal may be desirably containedin the aerosol and desirably delivered to the user. In such cases, itmay be advantageous to ensure that such coformer(s) are sufficientlyvolatile at the temperature of use of the electronic smoking article.Additionally, any degradation products produced via heating nicotinesalts, co-crystals, or salt co-crystals to the relevant temperature(i.e., the typical operation temperature of an electronic smokingarticle) should also be evaluated and taken into consideration duringproduct preparation and selection for a particular application. Inparticular, in certain embodiments, acid degradation products producedvia heating nicotine salts, co-crystals, or salt co-crystals to therelevant temperature should be evaluated and taken into consideration.

Accordingly, in certain embodiments, following preparation of thenicotine salts, co-crystals, or salt co-crystals described herein, theyare analyzed to evaluate whether the nicotine and/or coformer and/ordegradation products thereof transfer from the aerosol precursor to theaerosol. Such analysis can be conducted, for example, by highperformance liquid chromatography and/or gas chromatography of thecondensate collected from the aerosol. Both the presence and amount ofnicotine and/or coformer and/or degradation products thereof isevaluated to determine whether a given salt, co-crystal, or saltco-crystal is a good candidate for incorporation within an electronicsmoking article.

In still further embodiments, nicotine salts, co-crystals, and/or saltco-crystals disclosed herein may be incorporated within pharmaceuticalproducts. For example, a nicotine salt, co-crystal, or salt co-crystalcan be used as a replacement for, or in addition to, the nicotine innicotine-containing pharmaceutical products. Such products can be usedfor treatment of a wide variety of conditions, diseases, and disordersresponsive to stimulation of one or more types of nicotinicacetylcholinergic receptors (nAChRs). The products can be used to treatthose types of conditions, diseases, and disorders that have beenreported to be treatable through the use or administration of nicotineas an agonist of nAChRs. As such, the products can be used to treatvarious CNS conditions, diseases, and disorders, and the compositionsalso can be used as smoking cessation aids (i.e., as components of NRT).The combined amount of nicotine present (including nicotine present asthe salt, co-crystal, and/or salt co-crystal form and, optionally, anyone or more other forms of nicotine) is preferably that amount effectiveto treat some symptoms of, or prevent occurrence of the symptoms of, acondition, disease, or disorder from which the subject or patientsuffers. Exemplary conditions, diseases or disorders that can be treatedinclude cognitive disorders such as Alzheimer's disease and attentiondeficit disorder, schizophrenia, Parkinson's disease, Tourette'ssyndrome, ulcerative colitis, dry eye disease, hypertension, depression,overactive bladder, obesity, seven year itch/scabies, and hemorrhoids.Such products may also find use as a treatment to reduce stress or painand/or as a smoking cessation aid.

The shape of the pharmaceutical products can resemble a wide variety ofpill, tablet, lozenge, capsule, caplet, pouch and gum types of productsthat traditionally have been employed for the administration ofpharmaceutical types of products. The general nature of a representativecomposition can be soft or hard to the feel, or of intermediate softnessor hardness; and as such, the composition can be considered to bemalleable, flexible, chewy, resilient, brittle, or the like.Pharmaceutical products containing nicotine salts, co-crystals, or saltco-crystals as provided herein are not limited to oral products, andsuch compositions as creams (including salves, ointments, and pastes),liquids (e.g., sprays or enemas), and the like are also encompassed bythe present invention as well. In addition, the nicotine salts,co-crystals, and salt co-crystals disclosed herein can also beincorporated within various devices for delivery, such as inhalers(e.g., metered dose inhalers, dry powder inhalers, and nebulizers).Pharmaceutical products according to the present invention can contain,in addition to a nicotine salt, co-crystal, and/or salt co-crystal asdescribed herein, one or more pharmaceutically acceptable components,e.g., excipients (e.g., salts, sweeteners, fillers, flavorants,antiadherents, glidants, preservatives and antioxidants, surfactants,dyes or pigments, lubricants, and/or processing aids). The applicationas written focuses on the incorporation of novel nicotine salts,co-crystals, and salt co-crystals. However, it is noted that, in someembodiments, known nicotine salts can be employed in compositionsdisclosed herein to provide novel compositions and/or novel productsincorporating such compositions. For example, although not intended tobe limiting, known salts such as nicotine L-malate (CAS RN 253180-13-1),nicotine 4-acetamidobenzoic acid salt (CAS RN 110441-65-1), nicotine3-hydroxybenzoic acid (CAS RN 1644394-41-1, disclosed, for example, inInt. App. Pub. No. WO2015/006652), nicotine 2,5-dihydroxybenzoic acid(CAS RN 6012-21-1), nicotine 4-aminosalicylic acid salt(1-hydroxy-4-amino benzoic acid salt) (CAS RN 20334-41-2), nicotinesalicylic acid salt (2-hydroxybenzoic acid salt) (CAS RN 29790-52-1),nicotine phthalic acid salt (1,2-benzene dicarboxylic acid salt) (CAS RN88660-55-3), nicotine N-acetyl-4-aminosalicylic acid salt(N-acetyl-2-hydroxy-4-aminobenzoic acid salt) (CAS RN 900789-26-6),and/or nicotine di-L-(+)-tartrate dihydrate (CAS RN 6019-06-3) can beused in the compositions and products disclosed herein.

It is further noted that, although the application as written focuses onthe formation of nicotine salts, co-crystals, and salt co-crystals andon the incorporation of such formed nicotine salts, co-crystals, andsalt co-crystals into various products, it may be possible, in someembodiments, to form such nicotine salts, co-crystals, and saltco-crystals in situ. For example, nicotine can be combined with one ormore coformers as broadly described herein, and optionally, othercomponents (e.g., those types of components typically contained in theproduct to be formed), and a nicotine salt, co-crystal, or saltco-crystal is formed in situ. In other words, although it is oftenadvantageous for reasons disclosed herein, isolation and/or purificationof the nicotine salt, co-crystal, or salt co-crystal is not required inall embodiments prior to introduction into a product.

For example, in one embodiment, an aerosol precursor of an electronicsmoking article can be prepared by mixing a nicotine salt, co-crystal,or salt co-crystal with desired aerosol precursor components (e.g.,carriers and flavorants) or can be prepared by mixing nicotine, acoformer (e.g., an acid), and desired aerosol precursor components. See,for example, the methods of incorporating certain salts into aerosoldevices in Int. App. Pub. No. WO2014/182736 to Ploom, Inc., which isincorporated herein by reference.

Aspects of the present invention are more fully illustrated by thefollowing examples, which are set forth to illustrate certain aspects ofthe present invention and are not to be construed as limiting thereof.

EXPERIMENTAL General X-Ray Powder Diffraction (XRPD)

X-Ray Powder Diffraction patterns are collected on a Bruker AXS C2 GADDSdiffractometer using Cu Kα radiation (40 kV, 40 mA), automated XYZstage, laser video microscope for auto-sample positioning and a HiStar2-dimensional area detector. X-ray optics consists of a single Göbelmultilayer mirror coupled with a pinhole collimator of 0.3 mm. A weeklyperformance check is carried out using a certified standard NIST 1976Corundum (flat plate). The beam divergence, i.e., the effective size ofthe X-ray beam on the sample, is approximately 4 mm. A θ-θ continuousscan mode is employed with a sample—detector distance of 20 cm whichgives an effective 20 range of 3.2°-29.7°. Typically the sample isexposed to the X-ray beam for 120 seconds. The software used for datacollection is GADDS for XP/2000 4.1.43 and the data are analyzed andpresented using Diffrac Plus EVA v13.0.0.2 or v15.0.0.0.

Samples run under ambient conditions are prepared as flat platespecimens of powder, without grinding. Approximately 1-2 mg of thesample is lightly pressed on a glass slide to obtain a flat surface.Samples run under non-ambient conditions are mounted on a silicon waferwith heat-conducting compound. The sample is heated to the appropriatetemperature at 20° C./min and subsequently held isothermally for 1minute before data collection was initiated.

Single Crystal X-Ray Diffraction (SCXRD)

Data are collected on an Oxford Diffraction Supernova Dual Source, Cu atZero, Atlas CCD diffractometer equipped with an Oxford Cryosystems Cobracooling device. The data are collected using CuKα radiation. Structuresare typically solved using either the SHELXS or SHELXD programs andrefined with the SHELXL program as part of the Bruker AXS SHELXTL suite(V6.10). Unless otherwise stated, hydrogen atoms attached to carbonatoms are placed geometrically and allowed to refine with a ridingisotropic displacement parameter. Hydrogen atoms attached to aheteroatom are located in a difference Fourier synthesis and are allowedto refine freely with an isotropic displacement parameter.

Example 1. Salts of Nicotine with Mucic Acid

A screening experiment is first conducted to evaluate a solvent freemethod for the formation of a salt of mucic acid. The required amount ofmucic acid (relative to 100 nicotine) is weighed into HPLC vials.(S)-Nicotine is dispensed into each vial and the vials are shaken atroom temperature for three days. Solids are sampled and characterized byXRPD. As indicated in Table 1, the XRPD analysis results indicate thatthe solid formed in the vial includes a new crystalline phase form,indicative of the formation of a mucic acid salt.

TABLE 1 XRPD analysis of nicotine mucate Stoichiometry Form of(Nicotine:mucic acid) Product Results of XRPD Analysis 2:1 Solid Inputacid + new peaks 1:1 Solid Input acid + new peaks 1:2 Solid Input acid +new peaks

Various screening experiments were next conducted to evaluatealternative means for the preparation of mucate salts of nicotine, asthe slurrying method in neat nicotine was found to be challenging forrepetition on a larger scale.

An experiment is conducted to evaluate the preparation of a mucate saltvia slow evaporation from water. (S)-Nicotine (100 μL) is dispensed intoan HPLC vial along with enough mucic acid to make salts having a 2:1,1:1, and 1:2 ratio nicotine: mucic acid. Water is added in 100 μLaliquots until a clear solution is obtained or after 2000 μL has beenadded. The mixture of 2:1 nicotine: mucic acid produced a clear solutionafter 100 μL of water was added; however, no solid was isolated. Themixtures of 1:1 and 1:2 nicotine:mucic acid are poorly soluble in waterand did not produce a clear solution even after the addition of 2000 μLwater and these experiments were abandoned.

An experiment is conducted to evaluate the preparation of a mucate saltvia antisolvent-mediated salt formation. One equivalent of mucic acid(relative to 100 μL nicotine) is added to an HPLC vial and (S)-nicotine(100 μL) is dispensed into the vial. Ethanol is added in 1 mL aliquotsuntil a clear solution is obtained or after 5 mL has been added. Themixture did not produce a clear solution even after the addition of 5 mLethanol and this experiment was abandoned.

An experiment is conducted to evaluate the preparation of a mucate saltin tetrahydrofuran (THF). A saturated solution of mucic acid in THF isprepared and filtered prior to use. A portion (2 mL) of this stocksolution is added to each of three separate HPLC vials and a givenamount of (S)-nicotine is dispensed into each vial (25 μL, 50 μL, or 100μL). The vials are shaken at room temperature for three days and allthree vials contain clear solutions. The solutions are cooled to 4° C.for 24 hours and allowed to evaporate. No solids are formed.

Additional attempts to prepare the mucate salt from ethanol/water andisopropyl alcohol/water systems failed, again due to poor solubility ofthe acid. An attempt to prepare the mucate salt from DMSO/antisolventsystems also failed to produce the solid mucate salt.

Therefore, to prepare nicotine mucate on a larger scale, mucic acid (5.2g, 25 mmol) is suspended in (S)-nicotine (10 mL) and stirred at roomtemperature under argon overnight. To the resulting gummy mixture isadded a further 10 mL nicotine and the mixture is stirred for a further60 h. The solids formed in the mixture are isolated by filtration,washed with cold THF and heptane, and dried. The solid is furtherslurried in ethyl acetate for 50 hours at room temperature under argon,isolated by filtration, washed with ethyl acetate and heptane, and driedto give a pink solid (7.21 g, 94.2% yield).

The solid is analyzed by various techniques, including)(RFD, the patternof which is shown in FIG. 1. Representative peak listings for the XPRDof nicotine mucate are provided in Table 2.

TABLE 2 XPRD peak listings for nicotine mucate Angle d value IntensityIntensity Caption (2-Theta°) (Angstrom) (Count) (%)  7.072° 7.07212.48977 140 3.2  7.985° 7.985 11.0628 1106 25.5 10.879° 10.879 8.125881340 30.9 12.543° 12.543 7.05143 106 2.4 13.028° 13.028 6.78977 234 5.413.807° 13.807 6.4084 349 8.1 14.289° 14.289 6.19336 2315 53.4 15.009°15.009 5.89798 2642 61 15.449° 15.449 5.73081 2974 68.6 15.851° 15.8515.5866 1487 34.3 16.834° 16.834 5.26237 1121 25.9 17.237° 17.237 5.14037811 18.7 18.163° 18.163 4.88041 426 9.8 19.660° 19.66 4.51189 4333 10019.930° 19.93 4.45142 1130 26.1 20.412° 20.412 4.34734 3905 90.1 21.287°21.287 4.17062 404 9.3 21.714° 21.714 4.08949 1391 32.1 22.141° 22.1414.01166 1737 40.1 22.455° 22.455 3.95618 1021 23.6 22.796° 22.7963.89791 805 18.6 22.986° 22.986 3.86611 920 21.2 23.870° 23.87 3.724881759 40.6 24.614° 24.614 3.61396 437 10.1 25.149° 25.149 3.53815 130 325.642° 25.642 3.47127 209 4.8 26.135° 26.135 3.4069 714 16.5 26.874°26.874 3.31492 554 12.8 27.212° 27.212 3.27449 417 9.6 27.558° 27.5583.23418 707 16.3 27.833° 27.833 3.20282 423 9.8 28.202° 28.202 3.16177598 13.8 28.657° 28.657 3.11256 256 5.9 29.237° 29.237 3.05217 1221 28.229.498° 29.498 3.02568 739 17.1 30.001° 30.001 2.9761 1233 28.5 30.800°30.8 2.90074 1841 42.5 31.855° 31.855 2.807 551 12.7 32.525° 32.5252.75068 185 4.3 32.810° 32.81 2.72747 265 6.1 33.216° 33.216 2.69505 3067.1 33.611° 33.611 2.66427 243 5.6 34.144° 34.144 2.62388 504 11.634.499° 34.499 2.59766 597 13.8 34.999° 34.999 2.56169 629 14.5 35.577°35.577 2.52142 290 6.7 36.132° 36.132 2.48392 282 6.5 36.724° 36.7242.44524 506 11.7 37.341° 37.341 2.40627 533 12.3 37.756° 37.756 2.380721127 26 39.373° 39.373 2.28663 353 8.1 39.853° 39.853 2.26015 379 8.740.383° 40.383 2.23171 311 7.2 41.002° 41.002 2.19948 344 7.9 41.326°41.326 2.18297 291 6.7 41.681° 41.681 2.1652 275 6.3 41.873° 41.8732.15568 315 7.3

The sample is further analyzed by methods including ¹H NMR, as shown inFIG. 2, (indicating that the solid consists of 0.72 equivalents ofacid—true stoichiometry of this form is unknown); PLM (indicatingirregular birefringent particles, typically <10 μm); TGA (indicating 91%mass loss from 25-260° C. in multiple unresolved steps; DSC (indicatinga sharp endotherm onset at 123° C. (73 J/g) and a broad endotherm onsetat 133° C. (27 J/g)); and GVS (indicating water uptake of 60% from 0-90%RH, although the actual water uptake is likely higher, as equilibriumwas not reached at 90% RH). The solid is rather hygroscopic.

Example 2. Salts of Nicotine with 4-acetamidobenzoic Acid

A screening experiment is first conducted to evaluate a solvent freemethod for the formation of a salt of 4-acetamidobenzoic acid.4-Acetamidobenzoic acid (111 mg) is suspended in the minimum amount of(S)-nicotine required to produce a mobile slurry (400 μL). The slurry isshaken at room temperature for 48 hours. Resulting white, powdery solidsare isolated by filtration and are sampled and characterized by XRPD,which indicates a new crystalline form.

Screening is next conducted to evaluate alternative means for thepreparation of 4-acetamidobenzoate salts of nicotine, as the slurryingmethod in neat nicotine was found to be challenging for repetition on alarger scale.

An experiment is conducted to evaluate a solvent-based method for theformation of a salt of 4-acetamidobenzoic acid. The 4-acetamidobenzoicacid is dissolved in the minimum amount of THF (400 μL) and (S)-nicotine(1 eq.) is added. The solution is covered and left to stand at roomtemperature overnight, then at 4° C. for 24 hours and −18° C. for 24hours. Only trace solids were present in the mixture at each point. Thecover is removed and the solvent is allowed to evaporate, giving acrystalline solid. The solid is sampled and characterized by XRPD as acrystalline solid, and the results thereof are consistent with thosecalculated based on the single crystal structure of nicotine4-acetamidobenzoate salt (see FIG. 3).

On a larger scale, 4-acetamidobenzoic acid (5.55 g, 31 mmol) isdissolved in THF (280 mL) at room temperature. The slightly cloudysolution is passed through a 0.45 μm PTFE filter and then (S)-nicotine(5 mL, 31 mmol) is added in 1 mL aliquots. The resulting clear solutionis stirred at room temperature for 10 minutes and then concentrated toapproximately ⅓ its original volume. The solution is seeded with 2 mg ofpreviously prepared nicotine 4-acetamidobenzoate, causing rapidcrystallization to occur. The mixture is shaken at room temperature for5 minutes and allowed to stand for 1 hour. The solid is isolated byfiltration, washed with ethyl acetate and heptane, and dried to give5.42 g white solid (51% yield).

The solid is analyzed by XRPD, the pattern of which is shown in FIG. 3.FIG. 3 compares the experimental XRPD data, obtained at roomtemperature, against an XRPD pattern calculated from single crystalx-ray data at 100K. Representative peak listings for the (experimental)XPRD of nicotine 4-acetamidobenzoateare are provided in Table 3.

TABLE 3 XPRD peak listings for nicotine 4-acetamidobenzoate Angle dvalue Intensity Intensity Caption (2-Theta°) (Angstrom) (Count) (%) 4.648° 4.648 18.99512 671 8.7  8.876° 8.876 9.95463 983 12.8 10.034°10.034 8.80827 903 11.7 13.964° 13.964 6.33687 526 6.8 14.472° 14.4726.11543 2032 26.4 15.049° 15.049 5.88254 1779 23.1 15.741° 15.7415.62534 305 4 15.945° 15.945 5.55387 481 6.3 16.839° 16.839 5.26087 374948.7 17.346° 17.346 5.10841 289 3.8 17.854° 17.854 4.96415 7695 10018.628° 18.628 4.7595 928 12.1 20.134° 20.134 4.40667 6451 83.8 20.438°20.438 4.34193 1282 16.7 20.733° 20.733 4.28088 1033 13.4 21.288° 21.2884.17039 1956 25.4 22.516° 22.516 3.94566 329 4.3 22.739° 22.739 3.90742530 6.9 23.265° 23.265 3.82026 3867 50.3 23.661° 23.661 3.75728 162221.1 24.268° 24.268 3.66459 373 4.8 24.798° 24.798 3.58754 786 10.225.408° 25.408 3.50272 616 8 25.720° 25.72 3.46098 420 5.5 26.077°26.077 3.41442 216 2.8 26.864° 26.864 3.31606 1298 16.9 27.322° 27.3223.26157 212 2.8 27.633° 27.633 3.22553 233 3 27.878° 27.878 3.1977 7309.5 28.228° 28.228 3.15892 1077 14 28.544° 28.544 3.12464 683 8.928.882° 28.882 3.0888 299 3.9 29.189° 29.189 3.05699 839 10.9 30.051°30.051 2.97131 168 2.2 30.473° 30.473 2.93113 606 7.9 30.818° 30.8182.89909 677 8.8 31.745° 31.745 2.81647 321 4.2 32.221° 32.221 2.77598281 3.7 32.501° 32.501 2.75266 419 5.4 33.466° 33.466 2.67545 261 3.433.909° 33.909 2.64149 257 3.3 34.456° 34.456 2.60081 265 3.4 34.995°34.995 2.56197 246 3.2 35.655° 35.655 2.51608 150 1.9 36.128° 36.1282.48423 190 2.5 36.527° 36.527 2.45796 235 3.1 37.342° 37.342 2.40618194 2.5 37.766° 37.766 2.38014 359 4.7 38.199° 38.199 2.35413 361 4.739.177° 39.177 2.2976 445 5.8 39.579° 39.579 2.27516 415 5.4 40.298°40.298 2.23621 485 6.3 41.539° 41.539 2.17224 189 2.5

The solid is further analyzed by various techniques, including ¹H NMR(indicating that the solid consists of 1.04 equivalents of acid); PLM(indicating irregular birefringent laths up to 75 μm in length); TGA(indicating 64% mass loss from 25-360° C. in two unresolved steps); DSC(indicating a sharp endotherm onset at 134° C. (151 J/g) and a broadendotherm onset at 143° C. (43 J/g)); and GVS (indicating water uptakeof 5% from 0-80% RH and 20% from 80-90% RH). XRPD analysis following GVSindicates that the solid is unchanged.

Crystal structures obtained for two independent molecules of nicotine4-acetamidobenzoate are shown in FIGS. 4A and 4B. The crystal packing ofthe nicotine 4-acetamidobenzoate obtained is provided in FIG. 4C,wherein nicotine molecules are shown in grey and acid molecules areshown in black.

Crystallographic parameters for the isolated form are provided in Table4. The structure solution was obtained by direct methods, full-matrixleast-squares refinement on F² with weighting w⁻¹=σ²(F_(o)²)+(0.0575P)²+(1.5000P), where P=(F_(o) ²+2F_(c) ²)/3, anisotropicdisplacement parameters. Empirical absorption correction using sphericalharmonics, implemented in SCALE3 AB SPACK scaling algorithm. Absolutestructure parameter=0.04(16) (Also known as the Flack parameter, thisshould be approximately zero for the correct absolute stereochemistry,and approximately unity for the inverted absolute structure (within thestandard uncertainty). Cf Flack H D (1983), Acta Cryst. A39, 876-881).The SCXRD structure provided confirmation that the nicotine has Sabsolute stereochemistry. Final wR²={Σ[F_(o) ²−F_(c) ²)²]/Σ[w(F_(o)²)²]^(1/2)}=0.0976 for all data, conventional R₁=0.0356 on F values of6624 reflections with F_(o)>4σ(F_(o)), S=1.001 for all data and 471parameters. Final Δ/σ(max) 0.000, Δ/σ(mean), 0.000. Final difference mapbetween +0.193 and −0.207 e Å⁻³.

TABLE 4 Crystallographic parameters for nicotine 4-acetamidobenzoateMolecular formula C₁₉H₂₃N₃O₃ Molecular weight 341.4 Crystal systemMonoclinic Space group C2 a 19.6640(10) Å, α 90°, b  12.6374(8) Å, β96.063(5)°, c  14.2489(8) Å, γ 90°  V 3521.1(3) Å³ Z 8 D_(c) 1.288 g ·cm⁻³ μ 0.717 mm⁻¹ Source, λ Cu-K(alpha), 1.54178 Å F(000) 1456 T 100(1)KCrystal Colorless prism, 0.18 × 0.1 × 0.07 mm Data truncated to 0.80 Åθ_(max) 74.47° Completeness 99.5% Reflections 17816 Unique reflections7005 R_(int) 0.0227 Abs. Struct. Para. 0.04(16)

Example 3. Salts of Nicotine with Gentisic (2,5-hydroxybenzoic) Acid

A screening experiment is first conducted to evaluate a solvent freemethod for the formation of a salt of gentisic acid. Gentisic acid (95mg) is suspended in the minimum amount of (S)-nicotine required toproduce a mobile slurry (200 μL). The slurry is shaken at roomtemperature for 48 hours. Resulting pinkish solids are isolated byfiltration and are sampled and characterized by XRPD, which indicates anew crystalline form.

An experiment is conducted to evaluate a solvent-based method for theformation of a salt of gentisic acid. The gentisic acid is dissolved inthe minimum amount of THF (200 μL) and (S)-nicotine (1 eq.) is added.The solution is covered and left to stand at room temperature overnight,then at 4° C. for 24 hours and −18° C. for 24 hours. A clear solutionwas present in the mixture at each point. The cover is removed and thesolvent is allowed to evaporate, but resulted in no isolated solid.

On a larger scale, gentisic acid (4.75 g, 31 mmol) is dissolved in THF(50 mL) at room temperature. (S)-Nicotine (5 mL, 31 mmol) is added in 1mL aliquots and the resulting clear solution is stirred at roomtemperature for 10 minutes. The solution is seeded with 2 mg ofpreviously prepared nicotine gentisate, causing rapid crystallization tooccur and the mixture is stirred at room temperature for 10 minutes. Thesolid is isolated by filtration, washed with cold THF and heptane, anddried to give 7.20 g white solid (74% yield).

The solid is analyzed by)(RFD, the pattern of which is shown in FIG. 5.FIG. 5 compares the experimental XRPD data, obtained at roomtemperature, against an XRPD pattern calculated from single crystalx-ray data at 100K. Representative peak listings for the (experimental)XPRD of nicotine gentisate are provided in Table 5.

TABLE 5 XPRD peak listings for nicotine gentisate Angle d valueIntensity Intensity Caption (2-Theta°) (Angstrom) (Count) (%) 10.212°10.212 8.65523 277 3.4 11.663° 11.663 7.58125 1668 20.4 12.243° 12.2437.22334 902 11 13.000° 13 6.80452 3280 40 14.127° 14.127 6.26419 178 2.214.608° 14.608 6.05916 1682 20.5 18.273° 18.273 4.85113 2192 26.719.017° 19.017 4.66305 8195 100 19.393° 19.393 4.57338 2090 25.5 19.968°19.968 4.44301 1368 16.7 20.194° 20.194 4.39387 3896 47.5 20.551° 20.5514.3183 952 11.6 21.000° 21 4.22689 4159 50.8 22.096° 22.096 4.01964 247430.2 23.080° 23.08 3.85046 275 3.4 23.407° 23.407 3.79738 867 10.624.385° 24.385 3.64735 573 7 24.615° 24.615 3.61376 1518 18.5 25.231°25.231 3.52691 1904 23.2 25.884° 25.884 3.43935 902 11 26.191° 26.1913.39982 4509 55 26.837° 26.837 3.31935 1327 16.2 27.133° 27.133 3.28378390 4.8 28.545° 28.545 3.12455 362 4.4 30.390° 30.39 2.93891 897 10.931.056° 31.056 2.87737 1361 16.6 31.855° 31.855 2.80696 1458 17.832.241° 32.241 2.77428 303 3.7 33.375° 33.375 2.68254 368 4.5 33.825°33.825 2.64785 187 2.3 34.452° 34.452 2.60111 205 2.5 34.712° 34.7122.58224 257 3.1 35.111° 35.111 2.55381 417 5.1 36.392° 36.392 2.46677198 2.4 36.742° 36.742 2.44411 215 2.6 37.007° 37.007 2.42721 174 2.137.349° 37.349 2.40576 524 6.4 37.869° 37.869 2.37391 375 4.6 38.193°38.193 2.35451 541 6.6 38.592° 38.592 2.33106 143 1.7 39.651° 39.6512.27124 501 6.1 40.271° 40.271 2.23769 190 2.3 40.793° 40.793 2.21022510 6.2 41.644° 41.644 2.16701 404 4.9

The solid is further analyzed by various techniques, including ¹HNMR(indicating that the solid consists of 1.00 equivalents of acid); PLM(indicating irregular birefringent laths up to 100 μm in length); TGA(indicating 95% mass loss from 25-280° C.); DSC (indicating a sharpendotherm onset at 149° C. (102 J/g)); and GVS (indicating water uptakeof 0.3% from 0-90% RH). XRPD analysis following GVS indicates that thesolid is unchanged. The gentisic acid salt compares well to commerciallyavailable nicotine ditartrate dihydrate in terms of thermal stability.

A crystal structure obtained for a molecule of nicotine gentisate isshown in FIG. 6A. The crystal packing of the nicotine gentisate obtainedis provided in FIG. 6B, wherein nicotine molecules are shown in grey andacid molecules are shown in black.

Crystallographic parameters for the isolated form are provided below inTable 6. The structure solution was obtained by direct methods,full-matrix least-squares refinement on F² with weighting w⁻¹=s²(F_(o)²)+(0.0720P)²+(0.0060P), where P=(F_(o) ²+2F_(c) ²)/3, anisotropicdisplacement parameters. Empirical absorption correction using sphericalharmonics, implemented in SCALE3 AB SPACK scaling algorithm. Absolutestructure parameter=0.4(3). Final wR²={S[w(F_(o) ²−F_(c) ²)²]/S[w(F_(o)²)²]^(1/2)}==0.1342 for all data, conventional R₁=0.0472 on F values of2025 reflections with F_(o)>4s(F_(o)), S=1.004 for all data and 221parameters. Final D/s(max) 0.000, D/s(mean), 0.000. Final difference mapbetween +0.173 and −0.219 e Å³.

Collected data was not suitable for determination of the absoluteconfiguration, so the stereochemistry of the nicotine moiety was fixedas per the input material and as per the structure determined in Example2 (i.e., with the S enantiomer of nicotine).

TABLE 6 Crystallographic parameters for nicotine 2,5-dihydroxybenzoateMolecular formula C₁₇H₂₀ N₂ O₄ Molecular weight 316.35 Crystal systemMonoclinic Space group P2₁ A  8.1984(7) A, α 90°, B 10.9394(9) Å, β112.589(11)°, C  9.2257(9) Å γ 90°, V 763.94(13) Å³ Z 2 D_(c) 1.375 g ·cm⁻³ μ 0.812 mm⁻¹ Source, λ Cu-K(alpha), 1.54178 Å F(000) 336 T 100(1) KCrystal colorless plate, 0.10 × 0.05 × 0.02 mm, Data truncated to 0.80 Åθ_(max) 26.37° Completeness 99.5% Reflections 12079 Unique reflections6914 R_(int) 0.0778 Abs. Struct. Para. 0.4(3)

Example 4. Salts of Nicotine with 3-hydroxybenzoic Acid

A screening experiment is first conducted to evaluate a solvent freemethod for the formation of a salt of 3-hydroxybenzoic acid.3-Hydroxybenzoic acid (85 mg) is suspended in the minimum amount of(S)-nicotine required to produce a mobile slurry (200 μL). The slurry isshaken at room temperature for 48 hours. The resulting gum is sampledand characterized by XRPD (showing that the sample deliquesced).

On a larger scale, 3-hydroxybenzoic acid (4.25 g, 31 mmol) is dissolvedin THF (50 mL) at room temperature by stirring for 10 minutes.(S)-Nicotine (5 mL, 31 mmol) is added in 1 mL aliquots with constantstirring and the resulting clear solution is stirred at room temperaturefor 10 minutes. The solution is seeded with 2 mg of previously preparednicotine 3-hydroxybenzoate, causing rapid crystallization to occur andthe mixture is stirred at room temperature for 1 hour. The solid isisolated by filtration, washed with cold THF and heptane, and dried togive 4.81 g white solid (52% yield).

The solid is analyzed by XRPD, the pattern of which is shown in FIG. 7.Representative peak listings for the XPRD of nicotine 3-hydroxybenzoateare provided in Table 7.

TABLE 7 XPRD peak listings for nicotine 3-hydroxybenzoate Angle d valueIntensity Intensity Caption (2-Theta°) (Angstrom) (Count) (%) 12.655°12.655 6.98936 3944 68.2 12.994° 12.994 6.80778 459 7.9 14.792° 14.7925.98419 332 5.7 15.143° 15.143 5.84607 860 14.9 15.394° 15.394 5.751431564 27.1 18.324° 18.324 4.8377 4891 84.6 18.591° 18.591 4.76894 230139.8 19.304° 19.304 4.59425 417 7.2 20.186° 20.186 4.39555 5781 10020.814° 20.814 4.26426 5235 90.6 21.150° 21.15 4.1974 967 16.7 23.810°23.81 3.73403 686 11.9 24.265° 24.265 3.66505 273 4.7 24.796° 24.7963.58772 2158 37.3 25.216° 25.216 3.52901 3287 56.9 26.155° 26.155 3.4044576 10 26.494° 26.494 3.36162 2164 37.4 27.303° 27.303 3.26382 562 9.727.865° 27.865 3.19919 221 3.8 28.466° 28.466 3.13305 261 4.5 28.967°28.967 3.07994 418 7.2 29.874° 29.874 2.9885 556 9.6 30.331° 30.3312.94445 786 13.6 30.604° 30.604 2.91886 1324 22.9 31.235° 31.235 2.86129263 4.5 31.678° 31.678 2.82231 549 9.5 32.000° 32 2.79461 464 8 32.650°32.65 2.74042 255 4.4 33.667° 33.667 2.65992 466 8.1 34.283° 34.2832.61358 258 4.5 34.700° 34.7 2.58309 229 4 35.367° 35.367 2.53587 3806.6 35.868° 35.868 2.50164 167 2.9 36.176° 36.176 2.48103 176 3 36.547°36.547 2.45667 183 3.2 36.885° 36.885 2.43495 402 7 37.377° 37.3772.40403 187 3.2 37.654° 37.654 2.38696 164 2.8 38.101° 38.101 2.35996171 3 38.509° 38.509 2.3359 203 3.5 39.080° 39.08 2.3031 128 2.2 39.625°39.625 2.27266 327 5.7 39.960° 39.96 2.25439 217 3.8 40.481° 40.4812.22654 193 3.3 41.024° 41.024 2.1983 198 3.4 41.425° 41.425 2.17798 1462.5 41.762° 41.762 2.16119 234 4

The solid is further analyzed by various techniques, including ¹H NMR(indicating that the solid consists of 1.03 equivalents of acid); PLM(indicating irregular sharp edged particles); TGA (indicating 89% massloss from 25-360° C. in two unresolved steps); DSC (indicating a sharpendotherm onset at 123° C. (131 J/g)); and GVS (indicating water uptakeof 0.5% from 0-80% RH and 5% from 80-90% RH). XRPD analysis followingGVS indicates that the solid is unchanged.

Example 5. Salts of Nicotine with L-malic Acid

A screening experiment is first conducted to evaluate a solvent freemethod for the formation of a salt of L-malic acid. The required amountof L-malic acid (relative to 100 nicotine) is weighed into HPLC vials in2:1, 1:1, and 1:2 ratios of nicotine:acid. (S)-Nicotine is dispensedinto each vial and the vials are shaken at room temperature for threedays. Solids are sampled and characterized by XRPD.

An experiment is conducted to evaluate the preparation of a L-malic acidsalt via slow evaporation from water. (S)-Nicotine (100 μL) is dispensedinto an HPLC vial along with enough mucic acid to make salts having a2:1, 1:1, and 1:2 ratio nicotine: L-malic acid. Water is added in 100 μLaliquots until a clear solution is obtained or after 2000 has beenadded. All mixtures of nicotine and L-malic acid produced a clearsolution after 200 μL of water was added; however, no solid wasisolated.

An experiment is conducted to evaluate the preparation of a L-malatesalt via antisolvent-mediated salt formation. One equivalent of L-malicacid (relative to 100 nicotine) is added to an HPLC vial and(S)-nicotine (100 μL) is dispensed into the vial. Ethanol is added in 1mL aliquots until a clear solution is obtained or after 5 mL has beenadded. After the addition of 20004, of ethanol, a clear solution wasafforded. EtOAc was then added in 1 mL portions until either persistentcloudiness was noted or 10 mL had been added. After the addition of 3000μL, a material was noted to be oiling out. The mixture was placed at 4°C. overnight and, after this time, was observed to be a sticky gum. Themixture was then placed at −18° C. for a week and, after this time, wasobserved to be a sticky gum. The gum was placed in an incubator andmaturated between ambient temperature and 50° C. at 8 h intervals for aperiod of 1 week, after which time the mixture appeared to be a viscoussolution.

An experiment is conducted to evaluate the preparation of an L-malatesalt by freeze drying and subsequent maturation. Stock solutions areprepared by combining (S)-nicotine (120 μL) with one equivalent of theacid in water (12 mL). The solution is shaken at room temperature togive a clear homogenous phase. A portion of the relevant stock solution(1 mL) is dispensed into each of 10 vials, which are frozen andlyophilized overnight to remove water. An aliquot of maturation solvent(100 μL of acetone, EtOH, IPA, toluene, dioxane, IPAc, TBME, acetone+5%water, EtOH+5% water, IPA+5% water) is added to each vial and the vialsare shaken at room temperature for 4 days. The vial containing IPAprovided a solid malate salt as determined by XRPD. The vials containingIPAc and TBME were observed to comprise an oil/gum; all other vials wereobserved to comprise clear solutions.

To prepare nicotine L-malate on a larger scale, malic acid (2.84 g, 21mmol) is dissolved in THF (30 mL) by stirring for 10 minutes at roomtemperature. (S)-Nicotine (5.0 mL, 31 mmol) is added, causing instantprecipitation of a white solid. The slurry is seeded with 2 mgpreviously-prepared nicotine L-malate and stirred at room temperatureovernight. The solids formed in the mixture are isolated by filtration,washed with cold THF and heptane, and dried to give a white solid (5.78g, 92% yield).

The solid is analyzed by XRPD, the pattern of which is shown in FIG. 8.Representative peak listings for the XPRD of nicotine L-malate areprovided in Table 8.

TABLE 8 XPRD peak listings for nicotine L-malate Angle d value IntensityIntensity Caption (2-Theta°) (Angstrom) (Count) (%)  6.128° 6.12814.41077 546 6.6  7.343° 7.343 12.0284 2526 30.4 12.147° 12.147 7.280161328 16 13.082° 13.082 6.76194 197 2.4 14.671° 14.671 6.0332 8306 10015.444° 15.444 5.73289 2296 27.6 15.957° 15.957 5.54959 1551 18.716.238° 16.238 5.45436 1243 15 17.237° 17.237 5.1402 937 11.3 17.462°17.462 5.0747 2565 30.9 18.243° 18.243 4.85897 3377 40.7 18.594° 18.5944.7681 843.8 10.2 18.710° 18.71 4.73894 912 11 19.326° 19.326 4.589215039 60.7 19.736° 19.736 4.49465 528 6.4 20.308° 20.308 4.36932 269 3.221.395° 21.395 4.14979 406 4.9 21.713° 21.713 4.08969 3481 41.9 22.049°22.049 4.0282 6470 77.9 23.256° 23.256 3.82176 655 7.9 23.586° 23.5863.76907 260 3.1 24.404° 24.404 3.6445 1566 18.9 24.652° 24.652 3.60842414 29.1 24.999° 24.999 3.55907 2912 35.1 25.759° 25.759 3.45584 205724.8 26.302° 26.302 3.38568 1188 14.3 26.764° 26.764 3.32829 340 4.127.303° 27.303 3.26373 281 3.4 27.632° 27.632 3.22571 419 5 28.097°28.097 3.17334 259 3.1 28.636° 28.636 3.11478 724 8.7 28.830° 28.833.09429 1045 12.6 29.712° 29.712 3.00437 731 8.8 30.476° 30.476 2.930841466 17.6 30.965° 30.965 2.88562 533 6.4 31.231° 31.231 2.86168 395 4.831.928° 31.928 2.80076 310 3.7 32.266° 32.266 2.77221 296 3.6 32.901°32.901 2.72014 261 3.1 33.362° 33.362 2.68357 379 4.6 33.784° 33.7842.65102 587 7.1 34.096° 34.096 2.62746 358 4.3 34.928° 34.928 2.56677375 4.5 35.394° 35.394 2.534 943 11.4 35.778° 35.778 2.50772 320 3.936.037° 36.037 2.49025 224 2.7 36.762° 36.762 2.44282 469 5.6 37.168°37.168 2.41704 654 7.9 37.677° 37.677 2.38558 622 7.5 37.960° 37.962.36839 439 5.3 38.625° 38.625 2.32916 468 5.6 39.599° 39.599 2.27409315 3.8 39.951° 39.951 2.25488 226 2.7 40.808° 40.808 2.20948 237 2.941.183° 41.183 2.19021 193 2.3 41.591° 41.591 2.16965 279 3.4

The solid is further analyzed by various techniques, including ¹H NMR(indicating that the solid consists of 1.07 equivalents of acid); PLM(indicating irregular birefringent particles typically <25 μm); TGA(indicating 91% mass loss from 25-260° C.); DSC (indicating a smallendotherm onset at 107° C. (1 J/g), a sharp endotherm onset at 120° C.(120 J/g), and a broad endotherm onset at 168° C. (452 J/g)); and GVS(indicating water uptake of 70% from 0-90% RH, although the actual wateruptake was likely actually higher, as equilibrium was not reached at 90%RH). The small endotherm onset may be possible evidence of the existenceof a second polymorph. XRPD analysis following GVS indicates that thesolid deliquesced.

Example 6. Salts of Nicotine with 3,5-dihydroxybenzoic Acid

A screening experiment is first conducted to evaluate the formation of anicotine salt with 3,5-dihydroxybenzoic acid by crystallization fromneat nicotine. 3,5-Dihydroxybenzoic acid (25 mg) is combined with(S)-nicotine (100 μL) and the mixture is shaken at room temperatureovernight. The 3,5-dihydroxybenzoic acid dissolves in the nicotine; nosolid is observed.

An experiment is conducted to evaluate the preparation of a3,5-dihydroxybenzoic acid salt via crystallization from THF.3,5-Dihydroxybenzoic acid (˜40 mg) is dispensed into a vial and THF isadded in aliquots, with brief vortexing after each addition. Additionwas stopped when 10 volumes have been added, as a clear solution wasobtained. (S)-Nicotine (1 molar equivalent) is then added to the vialand the vial is shaken at room temperature overnight. The resultingmixture is a clear solution; no solid is isolated.

An experiment is conducted to evaluate the preparation of a3,5-dihydroxybenzoic acid salt via crystallization from water.3,5-Dihydroxybenzoic acid (˜50 mg) is dispensed into a vial and water isadded in aliquots, with 10 minutes of stirring at 80° C. after eachaddition. Addition was stopped when 3 volumes have been added, as aclear solution was obtained. (S)-Nicotine (1 molar equivalent, 52.6 mg)is then added to the vial and the vial is left to stand at roomtemperature overnight. After 24 hours, the mixture is still a clearsolution and is placed at 5° C.; however, no solid is observed evenafter evaporation of the liquid.

An experiment is conducted to evaluate the preparation of a3,5-dihydroxybenzoic acid salt via crystallization from ethanol.3,5-Dihydroxybenzoic acid (˜50 mg) is dispensed into a vial and ethanolis added in aliquots, with 10 minutes of stirring at 70° C. after eachaddition. Addition is stopped when 3 volumes have been added, as a clearsolution was obtained. (S)-Nicotine (1 molar equivalent, 52.6 mg) isthen added to the vial and the vial is left to stand at room temperatureovernight. After 24 hours, the mixture was still a clear solution and isplaced at 5° C.; however, no solid is observed even after evaporation ofthe liquid.

An experiment is conducted to evaluate the preparation of a3,5-dihydroxybenzoic acid salt via crystallization from acetone.3,5-Dihydroxybenzoic acid (˜50 mg) is dispensed into a vial and acetoneis added in aliquots, with 10 minutes of stirring at 50° C. after eachaddition. Addition is stopped when 10 volumes have been added, as aclear solution was obtained. (S)-Nicotine (1 molar equivalent, 52.6 mg)is then added to the vial and the vial is left to stand at roomtemperature overnight. A solid formed in the vial at room temperaturefollowing evaporation; however, attempts to characterize the solid byXPRD failed, as the solid turned to a gum. This preparation from acetoneis repeated to explore maturation as a method to induce crystallizationby mixing 50 mg 3,5-dihydroxybenzoic acid, 10 volumes of acetone, and 1equivalent nicotine in a vial. The resulting mixture is cycled betweenroom temperature and 50° C. at 8 hour intervals for a period of 2 weeks.A solid is obtained and analyzed by XPRD (indicating a new form) and ¹HNMR (indicating a 1:1 salt). This material is further analyzed, as thecrystals obtained allowed an SCXRD structure to be collected (indicatingthat the material is an anhydrous salt). The crystal structure isprovided at FIG. 13.

On a larger scale, 3,5-dihydroxybenzoic acid (5.66 g) is dissolved inTHF (56 mL) at 50° C. (S)-Nicotine (5.9 mL, 1 eq.) is added, followed byseeds of previously prepared nicotine 3,5-dihydroxybenzoate (about 1mg). After cooling to 25° C. and stirring for about 16 h, the solid isisolated by filtration, washed with heptane (2×2 mL) and dried undervacuum at room temperature for about 16 h to give 7.55 g (65% yield) ofwhite solid. The dihydrate form (nicotine 3,5-dihydroxybenzoatedihydrate) is prepared by placing anhydrous nicotine3,5-dihydroxybenzoate (100 mg) into an open glass vial and exposing thenicotine 3,5-dihydroxybenzoate to an atmosphere of 96% RH at 25° C. for16 h. The sample is removed from the vial and characterized by XRPD toconfirm that the dihydrated form has been obtained.

The change in form of the anhydrous 3,5-dihydroxybenzoate salt uponexposure to varying humidity levels is indicative of an ability for thissalt to exist in one or more hydrated forms. A GVS experiment appearedto show conversion to mono- and di-hydrated forms as well as suggestingthe existence of another anhydrous form (with GVS water uptake 0-90% RHof 10% for the anhydrous form). While VH-XRPD experiments confirmed theexistence of the dihydrate (exhibiting the same XRPD diffractogram asmaterial resulting from storage of Form 1 at 25° C./96% RH), it was notpossible to observe the putative monohydrate and alternative anhydrousform. The dihydrate was subsequently prepared by exposure of theanhydrous form to humidity (converted during storage at 40° C. and 75%relative humidity and at 25° C. and 96% relative humidity). Thermalanalysis of this (converted) form show that it can convert back to theknown anhydrate upon heating. No events thought to represent phasetransitions were observed in the DSC thermogram for any of the salts,the only events being apparent melts. Specifically, the anhydrous formexhibited a melt onset at 138° C. and the dihydrate form exhibitedendotherms from 50-100° C. and a melt onset at 137° C.

The anhydrous form is further analyzed by PLM (indicating irregularparticles typically <10 μm), and both the anhydrous and dihydrate formsare analyzed by ¹H NMR (indicating a 1:1 stoichiometry for both forms).A single crystal x-ray diffraction study is performed on the anhydrousnicotine 3,5-dihydroxybenzoate and the structure solved as shown in theellipsoid plot of FIG. 13 (this is the form made during the small-scalescreening study, which is a different form than that obtained during thelarger-scale production). A plot showing hydrogen bonding in theasymmetric unit of anhydrous nicotine 3,5-dihydroxybenzoate is providedin FIG. 14A and a plot showing crystal packing for this salt is providedin FIG. 14B.

Both solids (the anhydrous form and the dihydrate form) are analyzed byXRPD, the patterns of which are shown in FIGS. 9 and 11, respectively.Representative peak listings for the XRPD of anhydrous nicotine3,5-dihydroxybenzoate are provided in Table 9 and representative peaklistings for the XRPD of nicotine 3,5-dhydroxybenzoate dihydrate areprovided in Table 10.

TABLE 9 XRPD peak listings for anhydrous nicotine 3,5-dihydroxybenzoateAngle Intensity Intensity (2-Theta°) (Count) (%) 9.8 238 4.6 12.3 85016.6 12.7 1831 35.7 13.6 588 11.5 14.9 988 19.3 15.5 303 5.9 17.8 5125100.0 18.2 962 18.8 19.7 2631 51.3 20.2 1983 38.7 20.9 758 14.8 21.34907 95.7 23.6 394 7.7 24.5 3311 64.6 24.9 1274 24.9 25.8 1870 36.5 26.2362 7.1 26.6 244 4.8 27.3 503 9.8 28.4 159 3.1 29.0 298 5.8 29.4 477 9.329.8 1136 22.2 30.1 441 8.6 30.4 219 4.3 31.2 323 6.3 31.5 166 3.2 32.2452 8.8 32.6 202 3.9 32.9 489 9.5 33.8 194 3.8 34.8 218 4.3 35.5 227 4.436.0 253 4.9 36.3 378 7.4 37.0 135 2.6 37.6 261 5.1 38.7 300 5.9 39.9250 4.9 40.2 266 5.2

TABLE 10 XRPD peak listings for nicotine 3,5-dihydroxybenzoate dihydrateAngle Intensity Intensity (2-Theta°) (Count) (%) 10.7 3131 92.9 12.5 88426.2 12.7 274 8.1 13.4 1575 46.7 15.0 2036 60.4 16.5 203 6.0 17.2 3518104.3 17.3 2575 76.4 19.0 2608 77.3 21.4 3372 100.0 21.6 1152 34.2 22.22475 73.4 22.6 1210 35.9 22.9 1392 41.3 24.3 1835 54.4 25.1 2470 73.325.5 3201 94.9 25.8 618 18.3 26.2 278 8.2 26.5 442 13.1 26.8 542 16.127.1 357 10.6 27.8 195 5.8 29.2 539 16.0 29.4 629 18.7 29.7 1144 33.930.2 331 9.8 31.4 159 4.7 31.9 265 7.9 32.2 125 3.7 32.6 180 5.3 33.2338 10.0 33.9 195 5.8 34.4 260 7.7 34.9 379 11.2 35.3 148 4.4 35.7 2657.9 36.1 138 4.1 36.4 169 5.0 37.4 158 4.7 37.7 275 8.2 38.1 163 4.838.5 351 10.4 38.9 131 3.9 40.4 209 6.2 40.9 315 9.3 41.5 170 5.0 42.0451 13.4

The anhydrous form and the dihydrate form of nicotine3,5-dihydroxybenzoate are further analyzed by various techniques,including ¹H NMR, as shown in FIGS. 10 and 12, respectively. Note thatthe broad resonance at about 9.6 ppm in both of these NMR spectra isbelieved to arise from the COOH acidic proton and reflects itsenvironment in the DMSO solution in which it was analyzed, which is notnecessarily the same as in the solid. In the solid state, the proton isexpected to be on the nitrogen atom of the nicotine, as proton transferwill have occurred, but in the DMSO solution, the salt is understood tobe in equilibrium with the dissociated species.

Crystallographic parameters for the isolated form are provided below inTable 11. The structure solution was obtained by direct methods,full-matrix least-squares refinement on F² with weighting w⁻¹=/[(σ²(F_(o) ²)+(0.0659P)²+0.270P], where P=(F_(o) ²+2F_(c) ²)/3, anisotropicdisplacement parameters. Semi-empirical absorption correction usingdirect methods, implemented in SHELXTL. Absolute structureparameter=0.02(7). Final wR²=0.0992 for all data, conventional R₁=0.0383on F values of 6431 reflections with F_(o)>4s(F_(o)), S=1.050 for alldata. Final difference map between +0.186 and −0.224 e Å⁻³.

TABLE 11 Crystallographic parameters for nicotine 3,5-dihydroxybenzoateMolecular formula C₁₇ H₂₀ N₂ O₄ Molecular weight 316.35 CrystallizationTetrahydrofuran solvent Crystallization Maturation method Crystal systemMonoclinic Space group P2₁ a  7.84902(9) Å α 90° b 13.74501(18) Å β96.0438(11)° c 15.03350(17) Å γ 90° V 1612.87(3) Å³ Z 4 D_(c) 1.303Mg/m⁻³ μ 0.770 mm⁻¹ Source, λ Cu-K(alpha), 1.54178 Å F(000) 672 T 100(2)K Crystal colorless prism, 0.200 × 0.200 × 0.160 mm Abs. Struct. Para.0.02(7)

Example 7. Salts of Nicotine with 2,3-dihydroxybenzoic Acid

A screening experiment is first conducted to evaluate the formation of anicotine salt with 2,3-dihydroxybenzoic acid by crystallization fromneat nicotine. 2,3-Dihydroxybenzoic acid (˜25 mg) is combined with(S)-nicotine (100 μL) and the mixture is shaken at room temperatureovernight. The resulting solid material is sampled and characterized byXPRD (showing a new form). The study is repeated on a 100 mg scale, withthe solids produced being isolated by filtration, washed with heptane(2×1 mL) and characterized by XPRD and ¹H NMR (which indicated a 1:1stoichiometry).

An experiment is conducted to evaluate the preparation of a2,3-dihydroxybenzoic acid salt via crystallization from THF.2,3-Dihydroxybenzoic acid (˜40 mg) is dispensed into a vial and THF isadded in aliquots, with brief vortexing after each addition. Addition isstopped when 10 volumes have been added, as a clear solution isobtained. (S)-Nicotine (1 molar equivalent) is then added to the vialand the vial is shaken at room temperature overnight. The resultingmixture is a clear solution; no solid is observed.

An experiment is conducted to evaluate the preparation of a2,3-dihydroxybenzoic acid salt via crystallization from water.2,3-Dihydroxybenzoic acid (˜50 mg) is dispensed into a vial and water isadded in aliquots, with 10 minutes of stirring at 80° C. after eachaddition. Addition is stopped when 20 volumes have been added, as aclear solution is obtained. (S)-Nicotine (1 molar equivalent, 52.6 mg)is then added to the vial and the vial was left to stand at roomtemperature overnight. After 24 hours, the mixture is still a clearsolution and is placed at 5° C.; however, no solid is observed evenafter evaporation of the liquid.

An experiment is conducted to evaluate the preparation of a2,3-dihydroxybenzoic acid salt via crystallization from ethanol.2,3-Dihydroxybenzoic acid (˜50 mg) is dispensed into a vial and ethanolis added in aliquots, with 10 minutes of stirring at 70° C. after eachaddition. Addition is stopped when 3 volumes have been added, as a clearsolution is obtained. (S)-Nicotine (1 molar equivalent, 52.6 mg) is thenadded to the vial and the vial was left to stand at room temperatureovernight. After 24 hours, the mixture is still a clear solution and isplaced at 5° C.; however, no solid is observed, even after evaporationof the liquid.

An experiment is conducted to evaluate the preparation of a2,3-dihydroxybenzoic acid salt via crystallization from acetone.2,3-Dihydroxybenzoic acid (˜50 mg) is dispensed into a vial and acetoneis added in aliquots, with 10 minutes of stirring at 50° C. after eachaddition. Addition is stopped when 10 volumes have been added, as aclear solution is obtained. (S)-Nicotine (1 molar equivalent, 52.6 mg)is then added to the vial and the vial is left to stand at roomtemperature overnight. No solid is observed and the solvent is allowedto evaporate; however, no solid is observed even after evaporation.

To prepare nicotine 2,3-dihydroxybenzoate on a larger scale,2,3-dihydroxybenzoic acid (4.47 g) is dissolved in THF (8.9 mL) at roomtemperature. Although unsuccessful on a smaller scale (as noted above),(S)-nicotine (4.7 mL) is added, causing instant precipitation of acrystalline solid. The slurry is diluted with further THF (3 mL) andstirred at room temperature for 1 hour. The solid present is isolated byfiltration, washed with heptane (2×3 mL), and dried under vacuum at roomtemperature for about 60 hours to give an off-white solid (7.90 g, 86%yield). Although not intended to be limiting, it is believed that thefailed attempt at salt crystallization from THF on a small scale (withsuccess of salt preparation from THF on a larger scale) is due todilution effects. The small scale crystallization attempt was performedusing an excess of THF and it is believed that, under such conditions,the solid remained solubilized and no precipitate was observed due tothe presence of this excess of THF. However, with less THF relative tothe 2,3-dihydroxybenzoid acid in the large scale method, a solid wasformed.

The solid is analyzed by XRPD, the pattern of which is shown in FIG. 12.Representative peak listings for the XPRD of nicotine2,3-dihydroxybenzoate are provided in Table 12.

TABLE 12 XRPD peak listings for nicotine 2,3-dihydroxybenzoate AngleIntensity Intensity (2-Theta°) (Count) (%) 9.7 87 2.4 12.4 2824 77.912.5 3002 82.8 13.1 172 4.7 14.7 338 9.3 15.2 1117 30.8 15.5 475 13.118.3 3625 100.0 19.4 297 8.2 19.7 1542 42.5 19.9 209 5.8 20.3 2486 68.620.9 3179 87.7 23.7 268 7.4 23.9 360 9.9 24.9 3298 91.0 25.2 2149 59.326.2 820 22.6 26.5 1350 37.2 26.7 148 4.1 27.4 447 12.3 27.8 118 3.328.4 271 7.5 28.9 297 8.2 29.3 258 7.1 29.5 339 9.4 29.6 410 11.3 30.41392 38.4 31.2 179 4.9 31.8 321 8.9 32.0 314 8.7 32.7 217 6.0 33.3 3479.6 33.6 234 6.5 34.4 197 5.4 35.6 332 9.2 36.6 384 10.6 37.0 396 10.937.5 182 5.0 37.7 161 4.4 38.1 145 4.0 38.6 156 4.3 39.0 230 6.3 39.8290 8.0 40.6 181 5.0 41.1 273 7.5

The nicotine 2,3-dihydroxybenzoate solid is further analyzed by varioustechniques, including ¹H NMR (indicating that the salt has a 1:1stoichiometry); PLM (indicating irregular plates up to about 150 μm);TGA (indicating a 2-stage mass loss from 150° C.); DSC (indicating amelt onset at 157° C.); and GVS (indicating water uptake of 0.12% from0-90% RH).

Example 8. Salts of Nicotine with 1-hydroxy-2-naphthoic Acid

A screening experiment is first conducted to evaluate the formation of anicotine salt with 2,3-dihydroxybenzoic acid by crystallization fromneat nicotine. 1-Hydroxy-2-naphthoic acid (˜25 mg) is combined with(S)-nicotine (100 μL) and the mixture is shaken at room temperatureovernight. The resulting solid material is sampled and characterized byXPRD (showing a new form). The study is repeated on a 100 mg scale, withthe solids produced being isolated by filtration, washed with heptane(2×1 mL) and characterized by XPRD and ¹H NMR (which indicated a 1:1stoichiometry).

An experiment is conducted to evaluate the preparation of a1-hydroxy-2-naphthoic acid salt via crystallization from THF.1-Hydroxy-2-naphthoic acid (˜40 mg) is dispensed into a vial and THF isadded in aliquots, with brief vortexing after each addition. Addition isstopped when 10 volumes have been added, as a clear solution isobtained. (S)-Nicotine (1 molar equivalent) is then added to the vialand the vial is shaken at room temperature overnight. The resultingmixture is a clear solution and a solid salt is obtained afterevaporation (providing the same XPRD pattern as obtained by preparationin neat nicotine).

An experiment is conducted to evaluate the preparation of a1-hydroxy-2-naphthoic acid salt via crystallization from water.1-Hydroxy-2-naphthoic acid (˜50 mg) is dispensed into a vial and wateris added in aliquots, with 10 minutes of stirring at 80° C. after eachaddition. A solution of the acid in water was never obtained (after 20volumes of water were added). (S)-Nicotine (1 mol. eq.) was added andthe slurry was stirred at 80° C. overnight. No change in XRPD pattern ascompared with the acid was observed, indicating no formation of a saltform.

An experiment is conducted to evaluate the preparation of a1-hydroxy-2-naphthoic acid salt via crystallization from ethanol.1-hydroxy-2-naphthoic acid (˜50 mg) is dispensed into a vial and ethanolis added in aliquots, with 10 minutes of stirring at 70° C. after eachaddition. Addition is stopped when 10 volumes have been added, as aclear solution is obtained. (S)-Nicotine (1 molar equivalent, 52.6 mg)is then added to the vial and the vial is left to stand at roomtemperature overnight. A solid is observed in the vial at roomtemperature; however, attempts to characterize the solid by XPRD failed,as the solid turned to a gum. This preparation from ethanol was repeatedto explore maturation as a method to induce crystallization by mixing 50mg 1-hydroxy-2-naphthoic acid, 10 volumes of ethanol, and 1 equivalentnicotine in a vial. The resulting mixture was cycled between roomtemperature and 50° C. at 8 hour intervals for a period of 2 weeks. Onlya clear solution was obtained.

An experiment is conducted to evaluate the preparation of a1-hydroxy-2-naphthoic acid salt via crystallization from acetone.1-Hydroxy-2-naphthoic acid (˜50 mg) is dispensed into a vial and acetoneis added in aliquots, with 10 minutes of stirring at 50° C. after eachaddition. Addition is stopped when 10 volumes have been added, as aclear solution is obtained. (S)-Nicotine (1 molar equivalent, 52.6 mg)is then added to the vial and the vial is left to stand at roomtemperature overnight. No solid is observed and the solvent was allowedto evaporate; however, no solid was isolated even after evaporation.

To prepare nicotine 1-hydroxy-2-naphthoate on a larger scale,1-hydroxy-2-naphthoic acid (5.02 g) is dissolved in THF (10.0 mL) atroom temperature. (S)-Nicotine (4.3 mL) is added, followed by seeds ofthe desired salt form (˜1 mg), causing instant precipitation of acrystalline solid. The slurry is stirred at room temperature for 30minutes and the solid present is then isolated by filtration, washedwith heptane (2×2 mL), and dried under vacuum at room temperature forabout 16 hours to give a buff-colored solid (6.49 g, 69% yield).

The solid is analyzed by XRPD, the pattern of which is shown in FIG. 17.Representative peak listings for the XPRD of nicotine1-hydroxy-2-naphthoate are provided in Table 13.

TABLE 13 XRPD peak listings for nicotine 1-hydroxy-2-naphthoate AngleIntensity Intensity (2-Theta°) (Count) (%) 9.0 604 11.0 11.2 1708 31.314.4 1937 35.3 15.6 5486 100.0 16.1 2911 53.1 17.0 1309 23.9 18.0 2624.8 18.5 842 15.3 19.2 1469 26.8 20.5 6843 124.7 22.2 1125 20.5 22.55337 97.3 22.9 339 6.2 23.8 211 3.8 25.4 1251 22.8 25.7 1637 29.8 26.3606 11.0 27.1 3128 57.0 27.8 433 7.9 28.4 274 5.0 28.9 495 9.0 29.9 63311.5 30.2 375 6.8 30.6 435 7.9 31.0 98 1.8 31.3 218 4.0 32.3 185 3.432.6 407 7.4 32.7 297 5.4 33.0 165 3.0 34.0 416 7.6 34.9 493 9.0 36.2547 10.0 36.5 300 5.5 37.1 90 1.6 37.4 307 5.6 37.8 215 3.9 38.5 69312.6 38.8 437 8.0

The nicotine 1-hydroxy-2-naphthoate solid is further analyzed by varioustechniques, including ¹H NMR (indicating that the salt has a 1:1stoichiometry); PLM (indicating irregular particles up to about 100 μm);TGA (indicating a 2-stage mass loss from 130° C.); DSC (indicating amelt onset at 111° C.); and GVS (indicating water uptake of 0.16% from0-90% RH).

Example 9. Pyrolysis Studies

Several salts of nicotine, including nicotine mucate, nicotine4-acetamidobenzoate, nicotine gentisate, nicotine 3-hydroxybenzoate,nicotine L-malate, nicotine 3,5-dihydroxybenzoate, nicotine2,3-dihydroxybenzoate, and nicotine 1-hydroxy-2-naphthoate are pyrolyzedat 650° C. in helium to evaluate pyrolysis products generated from eachsalt upon heating. In all samples, high yields of nicotine aregenerated, indicating that nicotine is liberated from the salt at thiselevated temperature.

The instrumentation used in the experiment was a filament pyrolyzer inline with a GC/MS instrument. During the pyrolysis process, compoundstypically released (in addition to nicotine) were the decarboxylatedmolecules corresponding to the analyzed acid, free carbon dioxide, andwater. For most salts, no decomposition of nicotine is ob served.

Example 10. Salt-Containing Lozenges

Several salts of nicotine, including nicotine mucate, nicotinesalicylate, nicotine 4-acetamidobenzoate, nicotine gentisate, nicotine3-hydroxybenzoate, nicotine L-malate, nicotine 3,5-dihydroxybenzoate,nicotine 2,3-dihydroxybenzoate, and nicotine 1-hydroxy-2-naphthoate areincorporated into smokeless tobacco products in the form of lozenges.The lozenges can generally comprise components disclosed in U.S. Pat.App. Pub. No. 2013/0078307 to Holton, Jr., which is incorporated hereinby reference. For example, representative lozenges can comprise isomalt,maltitol syrup, flavorant(s), water, and a nicotinic compound (with oneor more of the nicotine salts, co-crystals, or salt co-crystalsdisclosed herein used in place of the nicotinic compounds disclosed inthe reference). The amount of nicotine salt, co-crystal, or saltco-crystal included in each lozenge is that amount sufficient to provide2 mg nicotine (adjusted based on the weight of the particular coformer).The sensory (e.g., taste and mouthfeel) characteristics and/or thestability of lozenges can, in some embodiments, be affected by theselection of nicotine salt, co-crystal, or salt co-crystal.

It is noted that, in some embodiments, one or more components arecommonly introduced in nicotine-containing lozenges to precludevolatilization of the nicotine therein (e.g., including, but not limitedto, citric acid). The nicotine salts, co-crystals, and salt co-crystalsdisclosed herein may, in some embodiments, be incorporated into alozenge without such a component, as providing nicotine in this formmay, itself, prevent volatilization of the nicotine.

Many modifications and other embodiments of the invention will come tomind to one skilled in the art to which this invention pertains havingthe benefit of the teachings presented in the foregoing description.Therefore, it is to be understood that the invention is not to belimited to the specific embodiments disclosed and that modifications andother embodiments are intended to be included within the scope of theappended claims. Although specific terms are employed herein, they areused in a generic and descriptive sense only and not for purposes oflimitation.

What is claimed:
 1. A nicotine salt or crystalline polymorphic formselected from the group consisting of: a salt of nicotine and mucicacid; a salt of nicotine and 3,5-dihydroxybenzoic acid; a salt ofnicotine and 2,3-dihydroxybenzoic acid; a crystalline polymorphic formof nicotine 1-hydroxy-2-naphthoate, wherein the form is characterized byan X-ray powder diffraction pattern having peaks at one or more of thefollowing 2-theta diffraction angles: 15.6, 16.1, 20.5, 22.5, and 27.1;a crystalline polymorphic form of nicotine 4-acetamidobenzoate, whereinthe form is characterized by an X-ray powder diffraction pattern havingpeaks at one or more of the following 2-theta diffraction angles:16.839, 17.854, 20.134, and 23.265; and a crystalline polymorphic formof nicotine gentisate, wherein the form is characterized by an X-raypowder diffraction pattern having peaks at one or more of the following2-theta diffraction angles: 13.000, 19.017, 20.194, and 21.000.
 2. Thenicotine salt or crystalline polymorphic form of claim 1, comprising asalt of nicotine and mucic acid, wherein the form is characterized by anX-ray powder diffraction pattern having peaks at one or more of thefollowing 2-theta diffraction angles: 14.289, 15,449, 19.66, and 20.412.3. The nicotine salt or crystalline polymorphic form of claim 1, whereinat least about 50% of the salt or crystalline polymorphic form is incrystalline form.
 4. The nicotine salt or crystalline polymorphic formof claim 1, comprising a salt of nicotine and 3,5-dihydroxybenzoic acid,wherein the form is an anhydrous form characterized by an X-ray powderdiffraction pattern having peaks at one or more of the following 2-thetadiffraction angles: 12.7, 17.8, 19.7, 20.2, 21.3, 24.5, 24.9, 25.8, and29.8.
 5. The nicotine salt or crystalline polymorphic form of claim 1,comprising a salt of nicotine and 3,5-dihydroxybenzoic acid, wherein theform is a hydrated form characterized by an X-ray powder diffractionpattern having peaks at one or more of the following 2-theta diffractionangles: 10.7, 13.4, 15.0, 17.2, 17.3, 19.0, 21.4, 21.6, 22.2, 22.6,22.9, 24.3, 25.1, 25.5, and 29.7.
 6. The nicotine salt or crystallinepolymorphic form of claim 1, comprising a salt of nicotine and2,3-dihydroxybenzoic acid, wherein the form is characterized by an X-raypowder diffraction pattern having peaks at one or more of the following2-theta diffraction angles: 12.4, 12.5, 15.2, 18.3, 19.7, 20.3, 20.9,24.9, 25.2, 26.5, and 30.4.
 7. An electronic smoking article comprisingan inhalable substance medium contained within a cartridge body and aheating member positioned to provide heat to at least a portion of theinhalable substance medium, wherein the inhalable substance mediumcomprises one or more of the nicotine salts or crystalline polymorphicforms of claim
 1. 8. The electronic smoking article of claim 7, whereinthe inhalable substance medium further comprises one or more ofglycerin, water, and a flavorant.
 9. The electronic smoking article ofclaim 7, wherein the amount of nicotine salt or crystalline polymorphicform is that amount sufficient to provide nicotine in an amount of about0.01 mg to about 0.5 mg per puff on the article.
 10. The electronicsmoking article of claim 7, wherein the amount of nicotine salt orcrystalline polymorphic form is that amount sufficient to providenicotine in an amount of about 0.05 mg to about 0.3 mg per puff on thearticle.
 11. The electronic smoking article of claim 7, wherein theamount of nicotine salt or crystalline polymorphic form is that amountsufficient to provide nicotine in an amount of about 0.1 mg to about 0.2mg per puff on the article.
 12. A smokeless tobacco product comprisingone or more of the nicotine salts or crystalline polymorphic forms ofclaim
 1. 13. The smokeless tobacco product of claim 12, selected fromthe group consisting of loose moist snuff (e.g., snus); loose dry snuff;chewing tobacco; pelletized tobacco pieces; extruded or formed tobaccostrips, pieces, rods, cylinders or sticks; finely divided groundpowders; finely divided or milled agglomerates of powdered pieces andcomponents; flake-like pieces; molded tobacco pieces; gums; rolls oftape-like films; readily water-dissolvable or water-dispersible films orstrips; meltable compositions; lozenges; pastilles; and capsule-likematerials possessing an outer shell and an inner region.
 14. Apharmaceutical product comprising one or more of the nicotine salts orcrystalline polymorphic forms of claim
 1. 15. The pharmaceutical productof claim 14, in a form selected from the group consisting of a pill,tablet, lozenge, capsule, caplet, pouch, gum, inhaler, solution, andcream.
 16. A lozenge comprising one or more of the nicotine salts orcrystalline polymorphic forms of claim 1 and at least about 50% byweight isomalt.